[Updated 6/2/2014. See below.] Myelofibrosis, a rare and potentially fatal type of leukemia, isn’t an easy disease to treat. The only drug that’s been approved by the FDA approval to treat it, Incyte’s (NASDAQ: INCY) ruxolitinib (Jakafi), attacks the symptoms rather than the cause, and often leaves patients needing blood transfusions.
Several companies are trying to develop treatments that either top Incyte’s drug or work with it—among them a startup called Promedior, which is trying to find out if its drug prospect can do what ruxolitinib can’t. And while there is a long way to go, the Lexington, MA-based company is taking a small step in that direction today.
Promedior today is giving a glimpse at the interim top-line results of a Phase 2 study of its lead drug, PRM-151, in myelofibrosis. These data are early: Promedior is only reporting numbers from a group of 18 patients who completed 24 weeks of treatment on its drug. But Promedior believes it’s seen enough to move PRM-151 into further testing. That’s because 7 of the patients had a meaningful improvement in a variety of myelofibrosis symptoms; 5 of them had a clinically meaningful reduction in the scarring of their bone marrow; and a “number” of them saw their levels of healthy blood cells and platelets improve while on treatment, according to CEO Suzanne Bruhn (pictured above).
“Patients who get anemic end up having to get a lot of blood transfusions, and that becomes a big part of their life,” she says. “So if we can stabilize things like hemoglobin, we might be able to get people off of their transfusions, and become transfusion-independent at some point.”
These are, of course, small signals. Promedior has many questions to answer, much more proof to accrue, and is just one of several companies—including Gilead Sciences (NASDAQ: GILD), Cell Therapeutics (NASDAQ: CTIC), and more—pursuing new treatments for myelofibrosis. But while many of those companies are focused on a similar approach—targeting the janus kinase, or JAK family of enzymes—Promedior is banking on a different approach to make it stand out.
Myelofibrosis occurs when the bone marrow starts producing abnormal stem cells that grow and divide too quickly, taking over the marrow and scarring the tissue. The bone marrow then isn’t able to produce blood cells, triggering anemia. Worse, the bone marrow’s job is taken up by the spleen, which balloons in size, causing pain. Ultimately, the disease can lead to death. About 18,000 people in the U.S. are diagnosed with myelofibrosis each year.
Ruxolitinib became the first drug approved to treat myelofibrosis in November 2011. It’s a pill that blocks the activity of enzymes known as JAK2 and JAK1, which are involved in signaling pathways that help the abnormal stem cells grow. The drug isn’t a cure, however. Ruxolitinib was approved based on its ability to alleviate various symptoms of myelofibrosis, such as reducing spleen size, and easing abdominal pain. It doesn’t halt, or reverse the bone marrow scarring that’s already taken place. Plus, because it impacts both healthy and mutated forms of JAK2 and JAK1, ruxolitinib is often associated with exacerbating the low platelet and blood cell counts that patients may already have.
Clearly, there is room for improvement, which is why so many other drugmakers are in on the race. Gilead, for instance, paid more than $500 million for YM Biosciences three years ago for a JAK-inhibiting myelofibrosis drug that showed signs of possibly reversing patients’ anemia. AstraZeneca and Cell Therapeutics are also among the companies that are developing variations of JAK inhibitors that, as Bruhn says, are trying to “get a little more benefit and a little less risk.”
So if Promedior can show that its drug can both impact bone marrow scarring, and reduce the anemia threat, it can enter the myelofibrosis discussion. Geron (NASDAQ: GERN), for instance, skyrocketed when its drug candidate, imetelstat, showed some ability to reverse fibrosis in a small trial—only to be pummeled by Wall Street after serious safety signals cropped up, leading to a partial clinical hold from the FDA.
Promedior thinks it has a shot to succeed because of its drug’s mechanism of action. PRM-151 is based on a naturally-occurring protein in humans called pentraxin-2 that works as a switch to halt and possibly reverse the formation of scar tissue. “[Pentraxin-2 works] really early in the process to kind of reset that whole environment.,” Bruhn says. The result, she says, is that cells that would otherwise develop into a form that causes damage instead wind up helping the bone marrow heal.
That’s all well and good, but where’s the proof? Promedior designed an adaptive, two-part Phase 2 trial: meaning Promedior first ran a small trial asking some big questions—like, is there a signal here that the drug is impacting fibrosis, how well does it work as a single agent and in combination with ruxolitinib, and should the drug be administered weekly or monthly? And, ultimately, do the answers warrant moving on to a bigger Phase 2?
Promedior is reporting the initial results of the first stage of that trial today. The company enrolled a total of 27 patients with either grade 2 or 3 fibrosis—a measure of their scarring—at the beginning of the study. They were broken into four groups and given either weekly or monthly doses of PRM-151 on its own, or in combination with ruxolitinib, over the course of 24 weeks.
Promedior took bone marrow biopsies at the beginning, middle and end of the trial. 18 patients have finished the study so far. Bruhn says three of the rest are still being tested, three withdrew, and three died, but that these were all older patients who had failed multiple JAK inhibitors, and that those withdrawals/deaths were largely no attributed to the drug.[Paragraph edited for clarity.]
“These folks are all very, very sick,” she says.
Promedior then measured the impact on bone marrow health, according to a scoring system that takes various side effects like spleen size and anemia into account (officially called the Myoproliferative Neoplasm Symptom Assessment Form). Seven out of the 18 patients had a 50 percent reduction in that score, and 5 of them saw their fibrosis reduced by at least one grade. A “number” of the patients on PRM-151 saw their levels of platelets and hemoglobin improve, though Bruhn wouldn’t specify how many. She says most of the side effects patients experienced were mild, and most were thought to be unrelated to PRM-151. [Paragraph edited for clarity.]
Still, this is a small sample size of patients, Promedior hasn’t even picked a dose for the next study yet, and the composite score isn’t an endpoint that would be used in a pivotal study. Further, though Promedior saw some patients with improvements to their fibrosis, others had signals of bone marrow health without anti-fibrotic evidence—so the company has plenty of things to figure out before it even starts the longer portion of its Phase 2 trial, let alone becomes a mover in the myelofibrosis field. But as Bruhn says, it’s a start.
“We’re excited,” she says. “This was a signal-finding, and we saw a signal in all four groups.”
Promedior was formed in 2006 and originally based in Malvern, PA. Bruhn, who spent most of her career at Transkaryotic Therapies (acquired by Shire in 2005) and had a hand in developing biologics for rare diseases like Fabre disease (aglsidase alfa, sold as Replagal) and Gaucher (velaglucerase alfa, sold as Vipriv), took over as CEO in May 2012. The company has raised a total of $76 million in venture dollars from the likes of Polaris Partners, Shire, and Morgenthaler.