Sometimes in biotech, and in life, you just need to stick it out long enough through the bad times to get to enjoy the good times. The folks at Cambridge, MA-based Infinity Pharmaceuticals (NASDAQ: INFI) have learned what that’s all about in the last few months.
Infinity suffered a painful setback a year ago, when its lead drug candidate failed in a mid-stage study for pancreatic cancer patients. It stung especially hard because the defeat came less than three years after another Infinity cancer drug flunked the final, most expensive phase of clinical trials.
After burning through more than $250 million of cash with no FDA-approved product on the market, Infinity could have easily found itself living on borrowed time.
Still, rather than making drastic cuts in a last-ditch bid to survive, Infinity ended up bouncing back to have what was probably the most successful year in its 12-year history: The company saw an astonishing six-fold rise in market value, from $5.98 a share on its lowest day of 2012, to $35.02 at yesterday’s close.
The boom was driven in part by increasing scientific validation of the PI3 kinase drug targets it is now focused on for treating cancer and autoimmune disease, and encouraging early results from its own drug, IPI-145.
The performance enabled Infinity to more than regroup. It raised about $260 million in a pair of stock offerings, renegotiated a couple of partnerships to regain full worldwide commercial rights to its lead drug, and began drafting an aggressive clinical trial plan that could put its PI3 kinase inhibitor in position to compete with tough players like Gilead Sciences (NASDAQ: GILD) and Novartis.
“We have had some ups and downs, and in this business you have to anticipate ups and downs. You plan so that you can have staying power,” Perkins says. “That’s how we approached building Infinity for the last decade. We’re not willing to risk the future of the enterprise on any single product. We’ve been disciplined in building the portfolio, and we’ve benefitted from it.”
The Infinity comeback is based on how investors view its position in the PI3 kinase field, which has been one of the hottest areas of cancer biology for several years.
Scientists have learned this pathway’s job is to stimulate a bunch of cell processes like proliferation, migration, and cell survival. When these normal functions get flipped into an overactive mode, people get cancer. An overactive set of PI3 kinases can also provoke the immune system to go haywire and attack healthy tissue—which leads to debilitating autoimmune diseases like rheumatoid arthritis and asthma.
One of the key lessons of the past few years is that straight-up blocking of the PI3k pathway may not be such a good idea. There are four distinct varieties the PI3 kinase, known as alpha, beta, delta, and gamma.
First-generation PI3k-blocking drugs tended to be made to hit all the various forms, but since alpha and beta variations are nearly ubiquitous on cells, blocking them prompted unwanted side effects, like excessive rises in patient blood sugar. That’s known as hyperglycemia in scientific jargon, and can lead to Type 2 diabetes.
More success has been seen with highly selective PI3k inhibiting drugs, especially Gilead Sciences’ idelalisib. This drug, which Gilead paid up to $600 million to acquire from Seattle-based Calistoga Pharmaceuticals, is designed to specifically bind with the delta variation, which is found entirely on cells of the immune system.
The drug has shown a promising combination of safety and effectiveness against several blood cancers, and is currently being tested in a final-stage clinical trial for chronic lymphocytic leukemia. Another drug, from Sunnyvale, CA-based Pharmacyclics (NASDAQ: PCYC), is aimed at a different molecular target on immune cells—Bruton’s tyrosine kinase—but has also shown compelling results for patients with some of the same blood cancers.
What Infinity brings to the table is still largely to be determined in clinical trials. But it licensed its own PI3 kinase inhibitor from San Diego-based Intellikine, a prolific developer of PI3 kinase drug candidates, which was acquired by Millennium:Takeda in 2011. The drug is designed unlike the others in clinical trials, to specifically hit both the delta and gamma variations, Adams says.
Infinity is working with scientific collaborators to better understand the roles of both delta and gamma in disease biology, but Adams says his belief is that “you need to hit both” to have a drug that’s active in both the innate and adaptive arms of the immune system, and to have a drug versatile enough to tamp down cell processes that lead to both cancer and autoimmune disease.
There’s no solid clinical proof yet that Infinity’s drug is a winner, but it’s clearly got a shot. Infinity’s drug was well-tolerated in an early study of 55 blood cancer patients, according to data presented in December at the American Society of Hematology meeting.
Three patients dropped out of the study because of adverse events, and there was one patient who had a serious case of neutropenia, a condition in which infection-fighting white blood cells are depleted. The study started at a low dose of 8 milligrams taken twice daily, which was enough to generate an anti-cancer response. Researchers tested the drug all the way up to 75 mg, and still hadn’t seen a maximum tolerated dose by the time of the ASH meeting.
“The data presented by Infinity at ASH was encouraging,” says Carol Gallagher, the former CEO of Calistoga Pharmaceuticals, the developer of the first delta-specific PI3 kinase inhibitor. “Similar to our early Phase 1 data with CAL-101 at Calistoga Pharmaceuticals [now Gilead’s idelalisib], their compound demonstrated interesting early efficacy and safety across a range of hematologic malignancies.”
Gallagher added, however, that while Infinity has an experienced team, it has a big challenge ahead. “With limited clinical data presented on the Infinity compound, it is too early to know whether their compound will differentiate itself from CAL-101, but history would tell us that first-in-class drugs in oncology win big and that it is difficult for second, third, and fourth entries to eclipse the significant adoption of the first-in-class agent.”
Data show the drug was able to completely block the PI3k delta enzyme, and block gamma at doses of 25 mg and higher. Although the study wasn’t designed to assess effectiveness at all the different doses, 19 of the 41 patients who could be evaluated (46 percent) had a partial or complete response to treatment as of the Nov. 20 data cutoff point.
“Patients feel good when they are on the drug,” Adams says. “There was no nausea, diarrhea, vomiting that’s often associated even with targeted treatments. Patients feel good, and that’s important for patient compliance.”
The safety of the drug is important, Perkins says, because Infinity wants to develop IPI-145 as a treatment that patients take chronically, potentially for years, for both cancer and autoimmune disease. A drug that’s taken for several years naturally needs to have fewer side effects than a cancer drug that people take in the last six to nine months of their lives. The profile of a chronic-use drug is also more attractive commercially, Perkins says.
“We’d like to make some of the diseases we’re studying into the next CML (chronic myeloid leukemia) in which patients basically live with their disease as a chronic condition,” Perkins says. “The diseases we’re studying have a patient population about six times as big as CML. For CML, [Novartis’s] Gleevec is about a $6 billion a year drug, and that’s because people stay on it for a long time. If you have a drug that provides efficacy at a low dose, and tolerability at a high dose, the hope is you can keep patients on it for a very long time.”
Infinity is in the midst now of crafting the studies that could propel it down that road. The company is now preparing to start a couple of mid-stage clinical trials, one of IPI-145 in rheumatoid arthritis, and the other for cancer, Adams says. Infinity is also moving ahead with another PI3k delta and gamma inhibitor, called IPI-443, which could have potential in different diseases or at different doses than the lead compound, Adams says.
Given how much cash Infinity is sitting on—enough to go into 2015—it should be able to design the next trials to be big enough to get a reliable answer about the drug’s effectiveness. Issues of trial design will be high on Infinity’s agenda in the early part of this year, and Perkins says she’s even on the lookout for new compounds that Infinity might license from others.
It’s quite a reversal of fortune from a year ago, when Infinity’s stock fell more than 30 percent in a day when a drug called IPI-926 failed in a pancreatic cancer trial. It seems like a long time ago now.
“Nobody likes to see others stumble and fail,” Adams says. “That schadenfraude thing, it’s not in my DNA, and it isn’t for most people in this business.”