It can take decades and billions of dollars to develop a drug, and its fate—and often that of its developer—rests in the outcome of clinical trials.
Just look at some of 2018’s biggest biotech stories. The failure of a closely watched cancer immunotherapy combination sent ripples through the sector and led several companies to change development strategies. The unexpected success of a prescription-grade fish oil in a massive study could change how heart disease is treated.
Next year will also bring critical results. One study could lead to the first-ever treatment for a growing liver disease epidemic. The results of a $2 billion Alzheimer’s program could shock skeptics and deliver a desperately needed treatment, or it could be a crushing blow to a key theory behind Alzheimer’s disease, which is already in deep dispute. In gene therapy, multiple studies could start moving the cutting-edge technology into broader patient populations and force a reckoning over sky-high drug prices.
Positive or negative, next year’s studies could have an impact on public health for years to come.
Part 1 is here. Part 2 will follow tomorrow. We couldn’t get to everything, of course. If you feel we’ve missed something, send us a note and make your case. [Editor’s note: Alex Lash, Corie Lok, and Frank Vinluan contributed to these reports.]
Disease Area: Alzheimer’s
Data Expected: 4Q 2019/2020
Why We’re Watching: Because of a change announced earlier this year, Biogen (NASDAQ: BIIB) might not have highly anticipated data for its experimental Alzheimer’s drug aducanumab by the end of 2019. But if it does, there could be no bigger biomedical news next year. In the U.S. alone, nearly 14 million people could be living with Alzheimer’s by 2050. It’s now the sixth-leading cause of death. The costs of care and productivity loss are in the billions of dollars.
But drugs like aducanumab, based on the “amyloid hypothesis”—that preventing or breaking up the clumps of beta-amyloid protein fragments in the brain can bring cognitive and physical improvement—have a horrendous track record. Every amyloid-targeting drug so far has failed, frequently after good early signals prompted investment in Phase 3 studies that cost hundreds of millions of dollars.
Biogen is making exactly that bet with aducanumab. Former CEO George Scangos, who green-lighted the Phase 3 program before stepping down, said in 2015 that Biogen was prepared to spend $2.5 billion.
Biogen needs to thread a difficult needle: Ramp up the dose enough to provide cognitive improvement, but not so much that it causes dangerous swelling in the brain, a side effect that has bedeviled other experimental Alzheimer’s drugs and that cropped up in aducanumab’s early tests.
The only hint so far from ENGAGE/EMERGE came in February, and it wasn’t well received. Chief medical officer Al Sandrock revealed that Biogen was adding more than 500 patients to the program because of “variability”—the trial needed to be even bigger to avoid statistical ambiguity. (That expansion might delay data until 2020.) The news sent Biogen’s stock down about 20 percent the next couple months. It has since recovered those losses and now sits roughly equivalent to where it was before the variability news.
One difference between Biogen’s efforts and the industry’s previous failures: Biogen is testing aducanumab in people with few, if any, Alzheimer’s symptoms. It’s a massive bet that attacking the buildup of amyloid clumps earlier in the disease will actually work, whereas treating more advanced patients is like slapping a bandage on someone who has nearly bled to death.
But some believe the amyloid hypothesis is on its last breath, and that R&D investment needs to flow more urgently to other areas of exploration. If aducanumab fails, that flow will quicken. If it succeeds, Biogen will have one of the most highly anticipated drugs ever, and clinicians might find themselves struggling to meet demand.
Disease Area: Duchenne muscular dystrophy
Companies: Sarepta Therapeutics, Solid Biosciences, Pfizer
Data Expected: 2019
Why We’re Watching: Despite significant advances the past few years—including the first-ever FDA-approved treatment, eteplirsen (Exondys 51)—Duchenne muscular dystrophy remains a deadly disease with a grim prognosis.
Duchenne afflicts some 300,000 boys worldwide, puts them in wheelchairs by their teenage years, and typically kills them at a young age from lung or heart problems. Steroids and eteplirsen, which is approved for a genetic subset of patients, can slow progression but don’t change the course of the disease.
Gene therapy just might. We’re keeping a close eye on three experimental treatments from Sarepta Therapeutics (NASDAQ: SRPT), Pfizer (NYSE: PFE), and Solid Biosciences (NASDAQ: SLDB), each to report clinical data next year.
Through each of these gene therapies, developers are engineering viruses to deliver micro-dystrophin, which is a smaller version of the muscle-protecting protein that Duchenne patients lack. The goal is to boost production via a one-time infusion.
Sarepta’s AAVrh74.MHCK7.micro-Dystrophin has produced promising early results, with the first four patients showing improved motor function and near-normal levels of micro-dystrophin. But the short test period and small number of patients were significant caveats.
In 2019, the picture should gain more clarity. Sarepta will report more data from the patients in its first study. It also plans to start a 24-patient, placebo-controlled trial by the end of the month, which Sarepta hopes could support an approval filing if the FDA agrees with its strategy. Rivals Solid and Pfizer are on Sarepta’s heels. Both intend to report data from early-stage studies in the first quarter of 2019.
Solid reported a setback early last year when the FDA temporarily halted testing of its gene therapy after a patient’s platelet and blood cell counts dropped dangerously low. The news was a cautionary tale for the advancing Duchenne gene therapies and, with gene therapy’s checkered past, remains a specter to keep an eye on as they quickly advance through clinical testing.
Disease Area: Hemophilia A
Company: BioMarin Pharmaceutical
Data Expected: TBA
Why We’re Watching: The reality of gene therapy for the chronic blood disease hemophilia isn’t far away now, and it all starts with a trial we’re watching called Gener8-1.
The company in charge, BioMarin Pharmaceutical (NASDAQ: BMRN), hasn’t said when, exactly, it will 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 cut the number of injections, which drug makers have been trying to do. Abicipar from Allergan (NYSE: AGN), for instance, is meant to be taken once every three months and should head for an FDA review next year. Same goes for brolucizumab from Novartis. And two drugs from Roche/Genentech—-faricimab and an implantable device that could dispense ranibizumab continuously over a matter of months—are in late-stage testing.
All of these treatments, however, would require chronic injections. Gene therapy could change that if a one-time dose could cause the eye to perpetually produce a VEGF-blocking protein. That’s why we’re highlighting RGX-314 from RegenxBio (NASDAQ: RGNX).
RegenxBio is facing an uphill battle. Gene therapy for wet AMD has been tried before several times, to no avail. And in a research note, Leerink analyst Mani Foroohar ticked off a number of hurdles for RGX-314. One: It’s injected into a different part of the eye than clinicians are accustomed to, a potentially riskier procedure. Two: Available drugs are very effective, so the bar for success is very high. Three: Cheaper biosimilar versions are on the way. Even if RGX-314 gets to market, reimbursement could be a huge challenge.
But the world—or at least drug regulators—are now ready for gene therapy. One for a different eye disease (Luxturna, for a form of inherited blindness) received FDA approval nearly a year ago. Other gene therapies are moving closer to market.
RegenxBio believes it has a technology advantage over previously failed programs. Its “vector,” or delivery tool, comes from University of Pennsylvania gene therapy pioneer James Wilson and has been successfully deployed in past gene therapy trials for other diseases. The hope is that vector, AAV8, may be more effective than the others that have failed in wet AMD.
Recent results from an ongoing Phase 1 study were encouraging. Larger trials are coming, as well, and they’ll be more telling. In November, RegenxBio said a Phase 2 study will start “as soon as possible,” with updates expected in early 2019. A spokesperson wouldn’t disclose additional details.
Disease Area: Diffuse large B-cell lymphoma
Data expected: 1H 2019 (L-MIND), 4Q 2019 (B-MIND)
Why We’re Watching: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, accounting for roughly 22 percent of those newly diagnosed in the U.S. each year, according to the Lymphoma Research Foundation. It’s also been one of the first entry points for CAR-T treatments from Novartis and Gilead Sciences (NASDAQ: GILD), which both nabbed DLBCL approvals in 2018. But data next year from MorphoSys (NASDAQ: MOR) could help the German company steal CAR-T’s thunder.
Newly diagnosed DLBCL patients are typically treated with a rituximab (Rituxan)/chemotherapy regimen known as R-CHOP, which wipes out many patients’ cancer. If R-CHOP isn’t the answer, patients move on to high-dose chemotherapy and a stem cell transplant, or more recently, CAR-T. But many patients aren’t eligible for stem cell transplants, and about half of those who are relapse again. While CAR-T has in some cases provided stunning results, it is expensive, logistically difficult, and brings dangerous side effects—some of them fatal.
MorphoSys is developing an alternative. Its experimental MOR208 is an antibody engineered to zero in on CD19, the same protein on cancerous B cells that CAR-T treatments target. At the American Society of Hematology meeting last month, MorphoSys presented data from a Phase 2 study, L-MIND. A combination of MOR208 and the blood cancer drug lenalidomide (Revlimid) kept the DLBCL of patients who had failed one to three therapies from spreading for a median of more than 16 months. That’s an “unprecedented finding in these patients,” JMP Securities analyst Konstantinos Aprilakis told Xconomy, and could lead to an approval as soon as 2020.
Will MorphoSys threaten CAR-T? We’ll need to see more data. The L-MIND results look superior to those seen with Gilead’s Yescarta, which kept cancers in check a median of 5.8 months in a study called ZUMA-1. But cross-trial comparisons have caveats. Evercore ISI analyst Bo Chen noted last month that the studies aren’t “directly comparable” because MorphoSys enrolled patients likely to have a better prognosis.
More long-term follow-up is needed, he said. Those results are coming. The full L-MIND results should come in the first half of next year. And beyond that is B-MIND, a late-stage study testing combinations of MOR28 and other drugs in DLBCL patients who can’t get high-dose chemotherapy or stem cell transplants. Data are expected by the end of 2019.
Disease Area: Postpartum depression (PPD)/Major depressive disorder (MDD)
Company: Sage Therapeutics
Data expected: January 2019 (PPD); TBA (MDD)
Why we’re watching: Depression is an epidemic. Some 18.1 million Americans are afflicted with major depressive disorder, the most common form, and it’s the leading cause of disability for people between 15 and 44.3 years old, according to the nonprofit Anxiety and Depression Association of America. Postpartum depression, too, is a big public health issue. It affects about 14 percent of women who give birth. Suicide from PPD is the most common form of maternal death after childbirth in the developed world.
Each condition has the same core problem. Available drugs might take weeks to kick in, if they work at all. A drug that could snap patients out of a deep depression quickly, then, could be hugely valuable. That’s what Sage Therapeutics (NASDAQ: SAGE) is trying to do with SAGE-217, which is being developed for both PPD and MDD. Its success or failure will be determined by data to emerge in 2019.
SAGE-217 works the same way as brexanolone, another Sage drug that the FDA could approve by March. Both target a neurotransmitter called GABA. In clinical testing, brexanalone showed it could quickly relieve symptoms of depression in women with PPD. But brexanolone requires a continuous, 60-hour infusion, during which the patient must be monitored by a healthcare professional; SAGE-217 is a pill. And unlike other depression drugs taken chronically, SAGE-217 is being tested as a two-week regimen meant to curb depression symptoms quickly. If it does so without worrisome side effects, Sage might have a blockbuster drug on its hands. (It should be noted, brexanolone caused some patients to abruptly lose consciousness, which troubled FDA scientists.) Stifel analyst Paul Matteis predicted SAGE-217 has “multi-billion dollar revenue potential” at its peak if it comes through, although analyst predictions of future revenues are historically overwrought.
There are always caveats in assuming that good results, which SAGE-217 produced in Phase 2 depression studies, will carry over into larger Phase 3 studies. It’s even more so with depression. Several promising drugs have been flummoxed by a pervasive placebo effect in their largest, final test. Another caveat: SAGE-217 hasn’t been tested specifically in PPD patients yet. The Phase 3 data in PPD should arrive in January. They’ll set the stage for a group of Phase 3 MDD studies that are just getting started. The first one, a placebo-controlled study of 450 MDD patients, is estimated to wrap up by November 2019, according to clinicaltrials.gov.
Sage hasn’t yet disclosed when it expects to report data, according to a spokesperson.
Check Xconomy tomorrow for Part 2 of our list, which will feature important trials of CRISPR gene editing technology, drugs for sickle cell disease, nonalcoholic steatohepatitis, spinal muscular atrophy, and more.