Many of biotech’s biggest stories in 2017 followed the highly anticipated data from clinical studies. There were monumental successes, like the first-ever approval of a genetically modified living cell therapy, the first FDA application for a gene therapy or a medicine using RNA interference. There were also stinging failures, such as the latest in a long line of hyped Alzheimer’s disease drugs to fall flat.
A year ago, Xconomy published a two-part piece looking ahead to key clinical results expected in 2017. With the new year just around the corner, we’ve come back with a fresh list to watch in 2018, studies in cancer, liver disease, anemia, spinal muscular atrophy, and much more. We’re also highlighting some key early tests of newer technologies just starting to make their mark.
So what’s to come? Read on to find out. Part 1 is here. Part 2 will follow later this week. [Editor’s note: Alex Lash, Corie Lok, and Frank Vinluan contributed to these reports.]
Disease: Lung Cancer
Company: Bristol-Myers Squibb
Data Expected: First half of 2018
Why we’re watching: Lung cancer is the second-leading cause of cancer death. Treatment is changing at a rapid pace as big drug makers compete with new immunotherapies. First, in October 2015, the FDA approved Bristol-Myers Squibb’s (NYSE: BMY) immunotherapy drug nivolumab (Opdivo) and Merck’s pembrolizumab (Keytruda) within days of one another for patients whose non-small cell lung cancer spread after chemotherapy. Then in 2016, pembrolizumab succeeded in a Phase 3 trial in newly diagnosed lung cancer patients, but nivolumab failed. Merck went on to have the first FDA-approved immunotherapy for those with a particular form of the disease that featured an abnormally high amount of the protein PD-L1.
Still, these drugs on their own only work in a fraction of patients. The race is on to do better, and that means testing pembrolizumab and nivolumab in combination with chemotherapies, other immune system-boosting drugs, and more. The FDA granted accelerated approval to a pembrolizumab-chemotherapy combination for first-line lung cancer in June, for instance. And just last month, Roche/Genentech’s immunotherapy atezolizumab (Tecentriq) succeeded in a Phase 3 trial when combined with chemotherapy and another Roche drug, bevacizumab (Tecentriq).
What’s on tap for 2018: Bristol will produce data from a 2,220-patient Phase 3 trial called Checkmate-227, which combines nivolumab and another of its immunotherapies, ipilimumab (Yervoy), in patients newly diagnosed with non-small cell lung cancer. The combination is already approved in melanoma.
Merck could present an interim look at Keynote-189, a confirmational study that tests pembrolizumab alongside chemotherapy (the combination was approved based on data from a smaller, earlier test). And AstraZeneca should update a study, Mystic, that combines two of its immunotherapy drugs, durvalumab (Imfinzi) and tremelimumab.
If positive, the results of the three studies could once again change how lung cancer is treated.
Disease Area: Melanoma
Companies: Merck, Incyte
Data expected: First half of 2018
Why we’re watching: Merck is running hundreds of trials with pembrolizumab, all with the KEYNOTE name. We’re watching this one for a couple reasons.
First, it’s part of the battle to treat the nasty skin cancer melanoma, which has been a bellwether of sorts for immunotherapies like pembrolizumab, known as checkpoint inhibitors. Used as solo therapies, pembrolizumab and its rivals notched their first approvals in melanoma. As with lung cancer, noted above, they have had great results, but in a limited number of patients. And as with other types of cancer, a search for immunotherapy combinations to boost that success rate continues at breakneck speed.
But combinations unleash the immune system with multiplied effects, as well, spurring worries about safety. A pair of checkpoint inhibitors from Bristol is the only approved combination approved so far for melanoma. But the combo, ipilumumab and nivolumab, is hard to tolerate. Merck thinks it can do better with pembrolizumab. The ongoing 700-patient KEYNOTE-252 study combines pembrolizumab with Incyte’s epacadostat, a drug that blocks an enzyme that tumors use to evade detection.
Which brings us to our second reason to watch. Known as IDO inhibitors, drugs like epacadostat have been the subject of what some people might consider irrational exuberance. This 2014 Genentech-Newlink Genetics tie-up came untied this year. But the drug that attracted Bristol’s billion-dollar attention in 2015 has produced what Bristol calls “encouraging” results in an early study of bladder and cervical cancer. (The acquisition has also triggered a big lawsuit.)
KEYNOTE-252 could be the first validation of Big Pharma’s IDO crush. It could also be good news for skin cancer patients who don’t have anywhere else to turn.
Disease area: Cardiovascular
Company: Esperion Therapeutics
Data expected: Mid-2018
Why we’re watching: Cholesterol-lowering drugs called PCSK9 inhibitors can significantly lower levels of low-density lipoprotein—the “bad” cholesterol. In 2015, the FDA approved alirocumab (Praluent) from Regeneron Pharmaceuticals (NASDAQ: REGN) and evolocumab (Repatha) from Amgen (NASDAQ: AMGN) as options for patients who can’t tolerate the standard-of-care statins, or need something more to control their cholesterol levels.
Not so fast, say insurers. They have resisted covering the expensive PCSK9 inhibitors—list price roughly $14,000 a year each—choosing to wait until massive studies prove the drugs can reduce the risk of heart attacks and strokes. In March, Amgen touted success in its huge study, and even offered insurers a refund if eligible patients have a heart attack. But evolocumab sales remain disappointing.
Regeneron’s big study, ODYSSEY OUTCOMES, could report within the next few months. Whichever way those results break, Amgen’s experience has made it clear that insurers want lower-cost alternatives. That’s why we’re keeping an eye on a Phase 3 trial from Esperion (NASDAQ: ESPR), which is testing a pill that combines its experimental bempedoic acid with Merck’s ezetimibe (Zetia), a cholesterol drug approved 15 years ago. Esperion is already playing up the possibility that the combination could be just as effective, but much cheaper, than PCSK9 blockers.
That aggressive marketing stance is based on Phase 2 data, which suggested that the pill, when combined with atorvastatin (Lipitor), reduced LDL levels by 64 percent after six weeks of treatment, which is in the ballpark of PCSK9 blockers. The 350-patient Phase 3 trial will provide a clearer picture, comparing the combination to bempedoic acid alone, ezetimibe alone, and a placebo.
Disease area: Beta-thalassemia/myelodysplastic syndrome
Company: Acceleron Pharma
Data expected: Mid-2018
Why we’re watching: People with the genetic blood disease beta-thalassemia normally need monthly blood transfusions to prevent deadly anemia. What’s more, they also need iron chelation therapy to flush out the iron overload those transfusions can cause. (That buildup of iron is often what kills them.)
New treatment options could be on the way, starting with an experimental drug from Acceleron Pharma (NASDAQ: XLRN) called luspatercept.
Luspatercept is a protein-based drug administered via regular subcutaneous injections that is meant to boost production of red blood cells in people with rare types of anemia. In Phase 2 studies, the drug showed it might help patients with either beta-thalassemia or another disorder that causes anemia, myelodysplastic syndrome, which doesn’t have any approved therapies. In the study, patients taking luspatercept required fewer transfusions and produced more oxygen-carrying hemoglobin. Acceleron and partner Celgene (NASDAQ: CELG) are now running luspatercept through three Phase 3 trials, two of which—BELIEVE (in beta-thalassemia) and MEDALIST (in myelodysplastic syndrome)—are expected to produce data in mid-2018. Success would put some pressure on nearby rival Bluebird Bio (NASDAQ: BLUE), whose gene therapy for beta-thalassemia, LentiGlobin, is also in late-stage testing.
Disease area: Spinal muscular atrophy
Data Expected: TBA, 2018
Why we’re watching: In December 2016, Biogen (NASDAQ: BIIB) and Ionis Pharmaceuticals (NASDAQ: IONS) made history with the FDA approval of nusinersen (Spinraza), the first-ever drug for spinal muscular atrophy. In its most severe form, the rare genetic disease can kill babies by the age of two. More moderate forms rob people of their ability to walk and function independently. The drug is a medical breakthrough: Nusinersen, an RNA-based therapy administered a few times a year, for life, through a spinal infusion, may slow the progression of multiple types of SMA.
Yet questions remain about the magnitude of its benefit, what percentage of patients it ultimately helps, and how it will impact patients over the long haul. These questions are amplified by nusinersen’s list price of $750,000 the first year, and $375,000 each year thereafter. As a recent editorial in the New England Journal of Medicine noted, there is room for improvement.
In 2018, improvement could emerge. Last month, Chicago-based AveXis (NASDAQ: AVXS) began a Phase 3 trial, STR1VE, of AVXS-101 in infants with the most severe form of SMA. AVXS-101 is a gene therapy—a one-time treatment meant to have long-lasting, if not permanent effects. Results from a small Phase 1 trial were head-turning: at 20 months of age, all 15 patients treated with AVXS-101 were alive and “event-free,” meaning they didn’t require a ventilator to breathe most of the day. No major safety problems cropped up.
STR1VE investigators say similar patients historically have an 8 percent survival rate without treatment. Will AVXS-101 similarly succeed in a larger, longer test? And if so, will it compete with nusinersen, or help boost its effectiveness as a combination? The cost of taking both drugs would likely be astronomical, but the argument whether the cost offsets the financial and social cost of not taking the drugs will be muted until we see the AveXis data.
Disease Area: Alzheimer’s
Company: vTv Therapeutics
Data expected: First half of 2018
Why we’re watching: The Alzheimer’s Association estimates there are 5 million Americans with the disease, which could reach 16 million by mid-century. There is also financial urgency, as the disease takes its toll on family members and other unpaid caregivers who themselves suffer health consequences and lost productivity. Each new failure to produce a treatment for Alzheimer’s disease underscores the urgency of the mission.
Most recently, the drug intepirdine, revived from the pharma dustbin by Axovant Sciences (NASDAQ: AXON) and backed by a massive IPO, failed to meaningfully boost patients’ cognition in a high-profile study.
The first big Alzheimer’s data of 2018 should come from a drug called azeliragon. Pfizer (NYSE:PFE) spent several years testing it until hitting a wall in 2011. The drug’s discoverer, TransTech Pharma, took it back and in 2015 began an 800-person Phase 3 study. (TransTech also merged with another North Carolina biotech and changed its name to vTv.) Jeff Kindler, who was Pfizer’s CEO until 2010, is now vTv’s executive chairman.
Positive or negative, the results will be notable. Azeliragon is the most advanced drug so far that blocks a brain receptor called RAGE (receptor for advanced glycation endproducts). Blocking RAGE, vTv believes, can attack Alzheimer’s three ways: disrupt the toxic accumulation of amyloid protein fragments; slow the breakdown of a different protein implicated in the disease, tau; and reduce brain inflammation. A chorus of researchers recently called for the Alzheimer’s field to consider multiple targets at once instead of the prevalent “one-size-fits-all” approach of fighting amyloid only.
There are caveats with azeliragon. vTv recruited its patients without a spinal fluid tap or PET scan to check for signs of the protein amyloid, although it conducted MRIs to check for other signs of damage. The company also revived azeliragon based on a retrospective look at earlier data that a subgroup of patients taking a lower dose did fairly well. Reinterpreting data is a controversial way to plan new, expensive studies. In Alzheimer’s, vTv isn’t the first to try. It’s a long shot that they’ll be the first to succeed.
Disease area: Non-alcoholic Steatohepatitis (NASH)
Company: Gilead Sciences
Data expected: First half of 2018
Why we’re watching: Nonalcoholic steatohepatitis (NASH), an increasingly common liver disease with no FDA-approved treatments, is one of the most competitive battlegrounds in drug development. Gilead Sciences has elbowed its way into the race with acquisitions, and 2018 will yield two updates that could determine how prudent those investments have been.
Typically due to sugary and fatty diets, NASH causes fat to build up in the liver. Inflammation and scarring can follow, and potentially a liver transplant, if the disease goes unchecked. NASH affects an estimated 2 to 3 percent of people in Western countries, and a group of companies including Intercept Pharmaceuticals (NASDAQ: ICPT), Gilead (NASDAQ: GILD), Allergan (NYSE: AGN), Bristol-Myers Squibb, and GenFit (EPA: GNFT) are all in the mix with experimental treatments. Intercept’s obeticholic acid (Ocaliva) is the furthest along, with Phase 3 data expected in 2019.
Gilead has three drugs that attack NASH in different ways. In 2018, we’re expecting Phase 2 results from two of them. The first is GS-9674, which came via the purchase of German biotech Phenex Pharmaceuticals in 2015. Like obeticholic acid, GS-9674 activates the FXR receptor, which helps break down fat and sugar to reduce fat accumulation.
The second data release is from a study testing, in combinations, all three Gilead NASH drugs: GS-9674, GS-0976 (acquired from Nimbus Therapeutics in 2016) and selonsertib. Earlier this year, Gilead reported encouraging phase 2 data for GS-0976 alone, showing that the drug, which blocks an enzyme called acetyl-CoA carboxylase, reduced fat buildup in the liver and lowered levels of a biomarker for liver scarring.
A Phase 3 trial of selonsertib called STELLAR won’t produce data for another few years. But by that time we should know much more about Gilead’s standing in the NASH race.
Disease area: Anemia
Data expected: TBA, 2018
Why we’re watching: When epoetin alfa (Epogen) was first introduced in the late 1980s, it was a huge advance in health care. A biologic drug could now help people with failing kidneys stave off anemia after iron no longer worked. Epogen and drugs like it have generated billions of dollars for Amgen (NASDAQ: AMGN) over the years, but they’ve also been tied to an increase in serious heart problems, leading to tighter restrictions from the FDA. A new wave of anemia-fighting pills may soon emerge as an alternative, if large-scale studies can prove them just as effective and safer than epoetin. The reward could be massive: The global market for such drugs is expected to reach $11.9 billion by 2020, according to a report by Allied Market Research.
The first big test is roxadustat, an experimental drug from San Francisco, CA-based FibroGen (NASDAQ: FGEN). Like rival vadadustat from Akebia Therapeutics (NASDAQ: AKBA), Fibrogen’s drug essentially tricks the body into thinking it’s in a high altitude, low-oxygen environment, which stimulates the production of more red blood cells. FibroGen and Akebia are each running large, expensive Phase 3 trials to compare their drugs against epoetin alfa. Each has aligned with larger pharmaceutical companies to help pick up the tab. FibroGen’s day of reckoning comes in 2018, when a slate of Phase 3 studies—Andes, Himalayas, and Sierras—produce data. Akebia should have three Phase 3 trials of its own completed by the end of 2019.