On Monday, Xconomy began our annual look ahead at clinical trials that could define biotech and have profound healthcare effects in the coming year. Today we’re circling back with the rest of the list, which includes studies of drugs for nonalcoholic steatohepatitis, cystic fibrosis, spinal muscular atrophy and more. Read on for the details. [Editor’s note: Alex Lash, Corie Lok, and Frank Vinluan contributed to these reports.]
Disease area: Nonalcoholic steatohepatitis (NASH)
Companies: Intercept Pharmaceuticals, Genfit
Data expected: 1H 2019 (REGENERATE), 2H 2019 (RESOLVE-IT)
Why We’re Watching: Sometimes diseases are preventable, but prevention isn’t likely to make a huge dent. There’s no starker example than bad diet and exercise habits leading to a fatty liver. Sometimes the condition advances into nonalcoholic steatohepatitis (NASH), and the liver becomes inflamed, stiff, and scarred. NASH can cause cancer and leads to thousands of liver transplants a year in the U.S. alone. The disease has now spread across the globe.
There is no current treatment for NASH. The race to provide one is at fever pitch, with Intercept Pharmaceuticals (NASDAQ: ICPT) of New York and French firm Genfit (NASDAQ: GNFT) in the lead. Intercept should be the first to present key Phase 3 data, and its once-a-day pill obeticholic acid (Ocaliva) already has FDA approval in a related liver disease.
In its 2,370-patient REGNERATE trial, Intercept has set out to show that obeticholic acid over 18 months can reduce liver scarring or achieve “resolution”—an agreed-upon abatement of various symptoms. It only needs obeticholic acid to hit on one or the other to prove successful, the company said when it amended the REGENERATE design in early 2017.
More broadly, Intercept hopes to improve patients’ long-term outlooks by comparing rates of death, hospitalization, cancer, and more among patients who are or aren’t on its drug. Intercept is testing two doses of its drug against placebo. Liver specialist Anjana Pillai of the University of Chicago told Xconomy in 2017 that doctors ideally want to see a NASH drug reduce all three of the disease’s hallmarks: scarring (also known as fibrosis), inflammation, and liver fat.
Genfit says its first cut at Phase 3 data will come late in the year, from the 2,000-person RESOLVE-IT study of its own once-a-day pill, elafibrinor. Unlike Intercept, Genfit is only shooting for NASH resolution. Reduction of fibrosis is a secondary study goal. (Like Intercept, Genfit will measure long-term outcomes; results will come much later and won’t likely be part of the company’s request for regulatory approval.)
Behind the two leaders are a bevy of companies, large and small, with NASH candidates. The list includes Gilead Sciences (NASDAQ: GILD), Allergan (NYSE: AGN) and its partner Novartis (NYSE: NVS), NGM Biopharmaceuticals and partner Merck (NYSE: MRK), Madrigal Pharmaceuticals (NASDAQ: MDGL), and Viking Therapeutics (NASDAQ: VKTX).
Roche, Pfizer (NYSE: PFE), Bristol-Myers Squibb (NYSE: BMY), 89Bio, and Akero Therapeutics are also in the mix. The need is large enough that the first drug to market will likely have stiff competition in the years to follow.
Disease Area: Rare genetic diseases
Companies: CRISPR Therapeutics, Editas Medicine, Sangamo Biosciences
Data Expected: 2019
Why We’re Watching: This year marked the first injection of a genome-editing medicine into a patient as part of a clinical trial. The early peek at the historic data—only four patients’ worth—didn’t go so well for the medicine’s developer, Sangamo Biosciences (NASDAQ: SGMO). Sangamo says more data from the early study, which aims to treat the rare, deadly Hunter syndrome, will come next year.
Sangamo uses its wholly-owned genome-editing technology, called zinc finger nucleases, which could explain why the company has flown under the radar. In other words, it’s not using CRISPR, the editing system that has spread to labs (even high-school labs) around the world.
In 2019, we could have our first CRISPR-in-humans results. (We’re not counting the unconfirmed claim of Chinese researcher He Jiankui that he edited human embryos and helped bring to life the world’s first gene-edited babies.) Two U.S. biotechs are launching medical trials with CRISPR: CRISPR Therapeutics (NASDAQ: CRSP) and Editas Medicine (NASDAQ: EDIT).
First up are CRISPR and its partner Vertex Pharmaceuticals (NASDAQ: VRTX) with a treatment for sickle cell disease called CTX001. The two were freed to start their trial in October when the FDA lifted a temporary hold on the study that paused enrollment. The phase 1/2 trial could include up to 45 patients with severe sickle-cell cases, which is marked by a lack of oxygen-carrying hemoglobin in the blood.
With CTX001, investigators will take patients’ blood stem cells, edit them to boost production of a fetal form of hemoglobin, and put those cells back into patients. It’ll actually be the second CRISPR Therapeutics study to start: an early-stage trial of CTX001 is already underway in Europe for patients with another hemoglobinopathy, beta-thalassemia.
Following closely behind is Editas Medicine (NASDAQ: EDIT), which the FDA cleared last month to start human studies of its experimental treatment EDIT-101. Editas and partner Allergan (NYSE: AGN) will test EDIT-101 in patients with Leber congenital amaurosis type 10, a rare genetic disease that causes vision loss. The CRISPR-based treatment will be injected directly into the retinas of 10 to 20 patients, where it is supposed to delete a disease-causing mutation in light-sensing retinal cells.
Unlike Sangamo and its zinc fingers that aim to edit the DNA in the liver cells of Hunter patients, CRISPR Therapeutics and Editas aren’t injecting CRISPR into the bloodstream. CRISPR Therapeutics is editing cells outside of the body, while Editas will inject CRISPR into the eye, a self-contained organ with reduced immune responses. Those strategies may help minimize some of the potential risks of CRISPR-based drugs that scientists have illuminated over the last year, like unintended edits and pre-existing immunity to key CRISPR components. But only clinical data will reveal how those risks play out in humans, which is why we are watching each study.
CRISPR Therapeutics could provide data in 2019, according to clinicaltrials.gov records. Both CRISPR Therapeutics and Editas declined to comment on timelines.
Disease Area: Cardiovascular
Companies: The Medicines Co./Alnylam Pharmaceuticals
Data Expected: 2H 2019
Why We’re Watching: It’s been a slog for a new class of injectable, cholesterol lowering medicines known as PCSK9 inhibitors. Approved in 2015, these drugs were hailed as a huge medical advance that could lower “bad” cholesterol, or LDL-C—particularly in people who have bad reactions to standard-of-care statins or who can’t lower their cholesterol enough with them.
But payers balked at the high prices, about $14,000 a year, and waited for evidence that the drugs could prevent heart attacks or strokes too. The developers of the two PCSK9 blockers, Regeneron Pharmaceuticals (NASDAQ: REGN) and Amgen (NASDAQ: AMGN), came through with huge studies and at least some evidence of those measures, but insurers still balked at reimbursing their drugs, alirocumab (Praluent) and evolocumab (Repatha).
The companies have since cut prices and worked creative deals with payers to try to move the needle. But now even lower-cost alternatives are in the works. A pill from Esperion Therapeutics (NASDAQ: ESPR) called bempedoic acid is headed for an FDA review in 2019. And we’ve got our eye on another experimental drug: inclisiran, from The Medicines Co. (NASDAQ: MDCO) and partner Alnylam Pharmaceuticals (NASDAQ: ALNY).
The proposed benefit is convenience. Alirocumab and evolocumab have to be administered once or twice a month, while inclisiran could potentially be injected just two or three times a year, which may help with patient compliance and lead to better control their cholesterol. MedCo has made a huge bet on that thesis: it jettisoned other programs, chopped its workforce, and raised $150 million in convertible notes to pay for the pricey late-stage studies underway.
In ORION-9, ORION-10 and ORION-11, patients with heart disease are getting either a placebo or four total doses of inclisiran over the course of 18 months. Data are expected in the second half of 2019.
Will the results matter to payers and physicians, or will they wait for the results of MedCo’s big “outcomes” study, akin to the ones Amgen and Regeneron have already run? And if inclisiran makes it to market, how will MedCo—which has seen the commercial struggles of Regeneron and Amgen—price the drug? Those are some of the questions ahead for MedCo, which expects to file for FDA approval by the end of 2019 if the ORION results are positive.
Like alirocumab and evolocumab, inclisiran aims to lower the levels of the protein PCSK9; lower levels correlate with better clearance of LDL from the blood. Inclisiran uses RNA interference—a method of stopping genes from producing disease-causing proteins—to prevent the liver from making PCSK9 in the first place. RNAi is a drug-making method that has just come of age after years of ups and downs. In August, Alnylam’s patisiran (Onpattro), for a rare genetic disease, became the first-ever FDA-approved RNAi medicine.
The ORION studies are the first big test of RNAi in a broader population and could signal that this new way of attacking disease could have a wider field of play.
Disease Area: Spinal muscular atrophy
Companies: Novartis, Roche
Data Expected: 1H 2019 (Novartis), 2019 (Roche)
Why We’re Watching: Things have begun to change for patients with the rare genetic disease spinal muscular atrophy. And that change is about to accelerate.
SMA robs people of their ability to walk and function independently. Some types of SMA can be lethal. There were no drugs available until late 2016, when the FDA approved nusinersen (Spinraza) from Biogen (NASDAQ: BIIB), an RNA-based treatment infused a few times a year. In clinical studies nusinersen showed the ability to slow the disease’s progression for people with multiple forms of the disease. A gene therapy and a pill may soon follow, setting the stage for multiple treatment options and a high-stakes commercial battle between Biogen, Novartis, and Roche.
Likely on its way first is a gene therapy, AVXS-101 (Zolgensma). Novartis paid $8.7 billion to buy AveXis and get its hands on the treatment, which offers long-lasting effects from a single infusion and is under regulatory review in the U.S., Europe, and Japan. But the data are only for SMA Type 1, the most severe form that afflicts infants.
Next year, Novartis aims to prove the gene therapy is effective in other groups, as Biogen has shown with nusinersen. Watch for two key studies: STRONG, for Type 2 patients; and SPR1NT, for patients with Type 1, 2, or 3 who have yet to show symptoms. Both are expected to produce data no later than the American Academy of Neurology’s big meeting in May 2019.
Then there’s Roche. Through an alliance with PTC Therapeutics (NASDAQ: PTCT), the company is developing a drug called risdiplam. Like nusinersen and AVXS-101, risdiplam works by boosting levels of the key protein, survival motor neuron, that SMA patients lack. But risdiplam is a liquid taken by mouth, or via a gastronomy tube for people who can’t swallow. It’s thus more familiar to doctors and payers than a one-time gene therapy (AVXS-101) that could cost millions of dollars—Novartis has said a $4 million price tag would be justified, given its benefits—or a complex spinal injection (nusinersen) that costs $750,000 for the first year and $375,000 each one thereafter.
Roche, of course, has to prove that risdiplam can hang with its two rivals. Nusinersen has by far the most extensive body of data, followed by AVXS-101. Risdiplam has produced encouraging early data from the trials FIREFISH, in Type 1 patients, and SUNFISH, in Type 2 and 3 patients. The same trials will produce more substantial information next year, and strong data could prompt Roche to ask for FDA approval in 2020. Two more studies—JEWELFISH (patients who have been treated with other SMA drugs) and RAINBOWFISH (pre-symptomatic patients)—have started, or soon will.
Disease Area: Sickle cell disease
Company: Global Blood Therapeutics
Trial: HOPE (Part A)
Data Expected: 2019
Why We’re Watching: Genome-altering medicines, like the one noted above and this one, could one day fix the mutated gene that produces sickle cell disease. But complicated biology, health economics, and other factors make that prospect highly speculative. Even in a best-case scenario, gene therapies are years away.
Meanwhile, roughly 100,000 people in the U.S., predominantly African-American, and millions more around the world with the disease need relief now. Sickle cell’s telltale malformed red blood cells clog vessels and can’t carry enough oxygen to muscles and other tissues. Patients suffer bouts of excruciating pain that often force hospital visits, as well as strokes, organ damage, and early death, even with the best treatment.
The new drug closest to market is voxelotor from Global Blood Therapeutics (NASDAQ: GBT), a once-a-day pill that targets a key blood protein, hemoglobin, and aims to prevent red blood cells from bending into the malformed sickle shape. GBT has reported interim results from the first portion (Part A) of a Phase 3 study called HOPE, and they showed the drug’s ability to meaningfully boost hemoglobin levels, compared to placebo.
Data from Part B of HOPE were supposed to come next and include results from patients reporting their own daily conditions on a smart phone app, but those plans were scuttled in June, as Xconomy reported. GBT said the data were too hard to read.
Despite those big changes in the structure of HOPE, GBT believes voxelotor is on the cusp of being just the third drug ever approved to treat sickle cell. Investors believe it, too. They sent shares soaring two weeks ago during the ASH meeting after the company said that the FDA only needed the Part A data, detailing the hemoglobin boost, to make a faster-than-normal approval decision.
So what’s to watch in 2019? Investigators updated the Part A data at ASH, and the results continued to impress. But GBT only reported data from about half the 270 patients planned for the study. A fuller data set will provide a clearer picture of voxelotor’s ability to reduce pain episodes. The more comprehensive results should also help assess safety, which has yet to be an issue with voxelotor.
Those updates are important. While sickle cell can be life-threatening—severity can depend on genetic profile and other factors—many patients have learned to manage their conditions and are not in imminent danger. The balance between risk and benefit could be tricky to navigate if safety problems emerge as the trial expands. “Oral therapies are less risky and more appealing to me than transplant and gene therapy,” says Cassandra Trimnell, a sickle-cell advocate and patient whom Xconomy profiled earlier this year. “I’m not in and out of the hospital like other people.”
Disease: Cystic fibrosis
Company: Vertex Pharmaceuticals
Data expected: 1Q 2019
Why We’re Watching: Vertex has already brought drugs to market that, for about 40 percent of patients with cystic fibrosis, can change the course of the deadly genetic lung disease. If it’s to expand its franchise to reach about 90 percent of patients and hold off the emerging competition, data expected shortly could be key.
Early this decade, Vertex emerged from a humiliating loss in the hepatitis C competition and reinvented itself around cystic fibrosis. In 2012, the FDA approved ivacaftor (Kalydeco), the first drug to address the cellular malfunction underlying CF. But ivacaftor only helps roughly 5 percent of CF patients with specific genetic mutations, meaning the vast majority of those with the disease don’t benefit from the drug. The company has been steadily pushing that number upwards by combining ivacaftor with other in-house CF drugs. After ivacaftor came ivacaftor/lumacaftor (Orkambi), in 2015, and then ivacaftor/tezacaftor (Symdeko) in 2018. Revenue from the three drugs generated $784 million last quarter alone for Vertex, whose shares are currently trading near all-time highs.
But competition is coming, and with memories of the hepatitis C debacle still fresh, Vertex needs to stay a step ahead. To do so, it is testing two three-drug cocktails that could potentially address up to 90 percent of CF patients. Once the data are in, Vertex will take the better combination to the FDA.
Good Phase 3 results are already in for one combination (VX-659/ivacaftor/tezacaftor), raising the bar for future competitors such as AbbVie (NYSE: ABBV) and Proteostasis Therapeutics (NASDAQ: PTI), Raymond James analyst Laura Chico noted recently. (Proteostasis should have data from an early study of its own three-drug combination shortly.)
We’ll see how high the bar goes early next year, when Vertex divulges Phase 3 results for the second three-drug regimen (VX-445/ ivacaftor/tezacaftor). Vertex expects to file an approval application for the better of its triplets by mid-2019.
Disease Area: Cancer/Infectious diseases
Data Expected: 2019
Why We’re Watching: After much hype and mystery about its messenger RNA drugs—an unproven technology with enormous potential—Moderna has finally gone public, sporting an $8 billion-plus valuation, and with it a chance to see how much substance is behind the hype.
Moderna has 10 drugs in human testing, including vaccines for infectious diseases or cancer. Some of them could produce their first data next year, according to clinicaltrials.gov. These updates won’t make or break Moderna, but they should offer glimpses into its technology. And that’s worth watching. Moderna has reported some clinical data before, but not as a public company closely scrutinized by analysts and investors. Every incremental update will help prove whether the company is, or isn’t, for real.
Further afield are the results from Moderna’s most advanced program, an experimental mRNA therapeutic for coronary heart disease called AZD8601. It’s the only Moderna drug in Phase 2 testing, and is owned by AstraZeneca (NASDAQ: AZN), which was the first big drug maker to buy into Moderna with a 2013 partnership.
AZD-8601 is a synthetic mRNA molecule meant to boost the production of a protein called VEGF-A, which stimulates blood vessel growth. The hope is that more VEGF-A will help people with cardiovascular disease regenerate heart tissue by improving blood flow. A Phase 1 study of AZD-8601 in men with type 2 diabetes showed that treated patients produced more VEGF-A than placebo and had better blood flow. In Phase 2, up to 33 patients are getting the drug injected into their hearts during coronary artery bypass surgery. Results could come in 2020, according to clinicaltrials.gov.
Other companies’ mRNA updates are also expected next year, adding to the early body of evidence for this new type of medicine. Translate Bio (NASDAQ: TBIO), which bought Shire’s old mRNA technology, is in the midst of a Phase 1/2 study for cystic fibrosis; interim data are expected in the second half of 2019. CureVac is running two Phase 1 trials, one for an immunotherapy for solid-tumor cancers and another for a rabies vaccine. And Germany’s BioNTech should have Phase 1 data next year for two cancer vaccines, for melanoma and triple-negative breast cancer.