Infinity Pharmaceuticals, Inc. (NASDAQ:INFI)
Barclays Global Healthcare Conference
March 12, 2013 9:30 am ET
Julian Adams - President of Research and Development
Good morning, everyone. So we have Infinity Pharmaceuticals next, and then we have Dr. Julian Adams to present to you on behalf of the company. I don't think Julian actually needs much introduction because he came from Millennium, and then we all know that Velcade today's commitment on the drug. So with that, I'll turn the podium to Julian.
Thank you. It's a privilege to join you this morning on this fine Sunday morning in Miami. Many of your colleagues, I'm sure, are out on the beach, enjoying themselves. So I'll give you a moment to read this. Okay, and I think today, we can say that Infinity is really poised to build the next great pharmaceutical company. We have all the ingredients: great clinical activity, the worldwide rights for all our product candidates and strong intellectual property, a great team. Execution is key to this, and finally, a strong financial position as well, and it all starts with our PI3-kinase delta/gamma inhibitor. IPI-145, we've envisaged 2 development packs, both in heme malignancies, as well as in inflammation and ongoing now are Phase I expansions in heme malignancies. These are some of the diseases we're covering, and we've begun and are conducting Phase IIa trial in asthma. And all of this taken together, if the stars align, has the potential to really be best-in-class for across-the-board and then a potential first-in-class in inflammation. Behind that, we've been very busy building the follow-on molecule. I'll just have a few words to say about IPI-443. It is also a delta/gamma inhibitor and also has the same potential to bifurcate both for heme malignancies and inflammation.
So this is the start of the show, IPI-145. As I've mentioned, it's exclusively potent PI3-kinase delta/gamma and extremely selective. We've tested the entire human kinome, and it really only -- its other PI3-kinase family. The clinical development status, as I've mentioned, both in inflammation and heme malignancies. I'll describe those in more detail to you, as well as the intellectual property, which is secured in the U.S. and pending review in ex-U.S.
So targeting B and T-cell malignancies, we reported early and encouraging data at ASH in 2012 this past December, and to-date, so far this year, we have completed the dose escalation and defined the maximum tolerated dose at 75 milligrams twice daily, and we've initiated 5 cohort expansions at that dose, and we plan on at least 2 additional trials later this year. This was the dose escalation schema. We started at a very low dose of 8 milligrams BID. As you can see, we've escalated all the way to 100 milligrams BID. At the 25-milligram dose level, we had already recorded impressive activities in CLL indolent non-Hodgkin's lymphoma and mantle cell lymphoma so we decided to amend the protocol and have an expansion cohort of up to 30 patients in CLL, iNHL and MCL, and completed most of that enrollment and presented some of those data at ASH. This had 2 benefits. One is to explore this low-dose where activity was clear. We have recorded and freed up the remaining escalations to explore some of the more difficult-to-treat malignancies, some of the more aggressive lymphomas, Hodgkin's lymphoma, for example, and T-cell malignancies as well, and you see we've achieved that. At 100 milligrams BID, we had 2 DLTs. This was a standard 3+3 design. We had a Grade 3 Rash, a Grade 3 ALT elevation. Both for protocol were held, the toxicities resolved, and both patients were dose-reduced to 75 milligrams BID, and did very well -- tolerated that dose and continue on that dose. So with 75 milligrams BID, formally defined as the MTD, we expanded per protocol up to 5 cohorts, in fact, 5 cohorts, including a reinvestigation of CLL in the lymphoma -- mantle cell lymphoma, T-cell malignancies, aggressive B-cell lymphomas, including DLBCL, the myeloid neoplasms, AML, myelofibrosis, aggressive CML, blast crisis in accelerated phase and the T and B-cell leukemia lymphomas. So I'll say more about that in a moment.
At ASH, we reported on the adverse events. As you can see here, there's no pattern of adverse event associated with the drug, lots of zeros. It looks like a well-tolerated drug at this point. What we did record was a great deal of biological activity. You can see here they're color-coded. Starting on the right, green for CLL, indolent lymphoma, mantle cell, aggressive lymphomas in orange, and on the far right, we have the T-cell lymphomas, where we saw signals of activity. We have recorded at least 3 CRs, and you can see a very high partial response rate based on CT scans at cycle 2.
Here's the vignette describing the CLL experience in all cases. We saw -- almost all cases, we saw a rapid lymphocytosis, which was concomitant with the resolution of lymphadenopathies, tumor shrinkage by CT scans. And then what we see here also is a relatively-rapid resolution of the lymphocytosis, meaning that cells that have regressed from the lymph node don't circulate in the blood, but very rapidly die of apoptosis in the blood compartment. This is very similar to the -- to other data reported by BTK inhibitors, but what you can see here is how rapid these responses are. And by cycle 2, we had 3 with formal responses, 6 of 11 with nodal responses, with a combination of 9 of 11 responses. The 10th patient responded in cycle 5 of the formal partial response and patient 11 sadly converted to rictus [ph] transformation. So a very, very high response rate, at least 82% as of the cutoff of 2 cycles. In addition, we look at duration of treatment. Now this being in early Phase I and insufficient data has been collected in terms of duration. But you can see at 2 months, over 90% of patients remain on study, very few discontinuations, one for an adverse event and for protocol. But basically, all patients who make it past 2 cycles across CLL and lymphoma mantle cell, continue on study.
Another vignette, in T-cell malignancies, as you know, many of the B-cell receptor therapies like the BTK inhibitors. BTK has not expressed in T-cells so we had a unique opportunity to look at cutaneous and peripheral T-cell lymphomas. And though it's only 7 patients with the data we've seen, 1 complete response, 1 partial response, some too early to assess, but looking like there's a signal there, particularly at the higher doses. So in the cohort expansion, we anticipate examining T-cell lymphomas more directly.
So in summation, where we've recorded, where we've seen activity, 3 complete responses in indolent lymphoma, T-cell lymphoma with an enteropathic lung metastases resolution of that lymphoma and a Hodgkin's lymphoma patient, then quite a number of partial responses, some stable diseases, particularly CLL, as they are stable due to their nodal responses, and very few patients with progressive disease. So this is a very active agent, at least, for 41 evaluable patients at this stage. And the time to response is also rather rapid. You can see between 2 and 3 cycles. As I showed you the safety profile as well, notably what was not on that profile were GI toxicities. So patients handle the drug very well, feel good on the drug and as their lymphadenopathies resolve, as their tumor shrinks, they tend to feel better and better, are gaining weight, are experiencing more energy, less fatigue, and so this drug appears to be both active, well-tolerated and patients feel -- and has a rapid onset of action. So active, as I said, across a range of B-cell malignancies, as well as now T-cell lymphoma, first to show that kind of activity. As I said, the responses are rapid and patients do remain on study, particularly patients who've made it past 2 cycles, and at least to date, we've met our goal of dose escalation, establishing 75 milligrams BID as the maximum tolerated dose.
So let me switch now briefly to our opportunity in the inflammatory diseases. We ran a -- both a single ascending dose study that was doubled-randomized, double-blind and placebo-controlled, and Part 2 of the study was a multiple ascending dose for 14 days treatment. Patients were treated with 1, 2 and 5 milligrams BID or twice daily, and 1 cohort was reserved for 10 milligrams once daily, and the objectives, of course, are tolerability, PK, pharmacodynamics, following single and repeat doses. 84 subjects were evaluated, and we presented these data at ACR 2012 last November. The drug was very well-tolerated. No differences between placebo and treatment groups. No signs or symptoms -- overt symptoms at any dose level. No opportunistic infections. The drug was very well handled, and no laboratory findings of any kind, including EKGs, liver panels and blood panels. So this enabled the first Phase II study -- Phase IIa study in allergic asthma. Approximately 30 patients are planned for the study. The study has commenced and has enrolled, and patients are double-blind, randomized, placebo-controlled, with a crossover in this study. They're randomized one-to-one. Each patient is screened for sensitivity to an allergen, randomized either to drug or placebo, pretreated for 14 days and then is challenged with an antigen provocation directly to the lung, and then there's a washout period, and patients are crossed over. If they got drug, they then get placebo. Again, it's all blinded, and we are awaiting the end of the study to unblind the various cohorts.
We are studying several cohorts to try to identify the dose range that we wish to study in the future, and the activity endpoints of FEV1 or forced expiratory volume in 1 second, a standard measure way - measure of lung function, as well as airway hyper-responsiveness and other markers of inflammation are part of this -- the secondary endpoints. So we're very excited about this study. It is not the intended eventual treatment population. We are going for the severe -- the moderate and severe asthmatics, but it's certainly the entry point to establish the dose range for activity in asthma. These data were supported by pre-clinical work in which we -- did a very similar kind of study in rats. We sensitize rats to ovalbumin, then instill ovalbumin into the trachea of rats and look at the inflammatory cell influx, in this case, the eosinophils entering the lung, and you can see that the vehicle or the very low-dose not active, but at doses as low as 0.3 milligrams per kilo, all the way to 10 milligrams per kilo. We had a profound effect on the inflammatory cells invading the lung, and that really is the story of asthma. In asthma, the airways are hyper-responsive, but also, it's the inflammatory cells that release the mediators and the influx of those cells that propagate the disease.
Similarly, we are planning and about to initiate a Phase II trial in RA. This is a very robust trial, that if successful, is designed to support a Phase III development. It's patients with moderate severe RA. It's quite a number of dose cohorts compared with placebo. It's, of course, double-blind, randomized, placebo-controlled and it will be multi-institutional in many countries, and it is really designed to evaluate safety and activity at multiple doses. And it too had very strong preclinical activity. This is an experiment in collagen-induced arthritis. Rats sensitized to collagen are then challenged with collagen, and we measure on the Y-axis the ankle diameter. So by day 10, you have active disease, and the various cohorts are treated either with vehicle or ascending doses of IPI-145. You can see a very nice dose response relationship. Here, Enbrel was used as a positive control.
We also did secondary analyses like x-ray, histology, cytokines in the joint tissue, and this was reported recently at the New York Academy of Sciences, and it is right now in press -- excuse me, submitted for publication, and it was also presented in much more detail at the Keystone meeting a couple of weeks ago. So again, very encouraging for activity in a TH1-mediated disease, rheumatoid arthritis; asthma being a TH2-mediated disease, and we know that the PI3-kinase acts as -- blocks the differentiation of Th0 to Th1 and Th2 so both arms of the inflammatory system.
Now we are not quiet in the lab. We mean for this to be a very important franchise in terms of PI3-kinase development so we've developed a second molecule, IPI-443. As I've mentioned, 443 has very similar characteristics for suppression of delta, also an exquisitely-potent drug in the low -- in 20 picomolar range, similar to IPI-145. The only difference we can measure at this point is it's slightly more potent for gamma so it's a more balanced delta/gamma inhibitor. These are Kds being reported, and this enables us to broaden the portfolio, to give us optionality, to develop 2 molecules both in heme and inflammation.
The next topic I'd like to close with is retaspimycin hydrochloride. This is our potent heat shock protein 90 inhibitor, and its functioning cancer cell is a -- has a chaperone to -- which is necessary for the stability of many of the misfolded proteins and to maintain protein homeostasis in the cell because the cancer cell is subject to genotoxic stress, environmental stress. It has many misfolded proteins, and the inhibition of Hsp90 would make those -- should make those cells much more susceptible to combinations with, for example, other chemotherapeutic agents. Again, we have a very selective and potent inhibitor and strong intellectual property. The key trial in this investigation after several years of study and based on Phase I, strong Phase I data, was to develop a trial, rather large Phase II trial, I should say, 226 patients. These are in heavy smokers, at least 15-pack years, with second or third line non-small cell lung cancer, who are naive to docetaxel treatment. They're randomized one-to-one docetaxel plus retaspimycin hydrochloride versus docetaxel plus placebo and we are following up the endpoint. The primary endpoint is overall survival. It's a co-primary endpoint; in fact, overall survival in the whole population or overall survival in the squamous cell population. And secondary endpoints include a proprietary predictive biomarker, which we have not disclosed, PFS and overall response rate. And enrollment was completed late last year, and we anticipate being able to report topline data in the first half of 2013.
So it remains for me to close with our financial highlights. As you can see, we finished 2012 with just over $325 million in cash and investments, a very healthy financial picture. Our operating expenses range between $115 million and $125 million, which is the same as our net loss. We have no revenue, and we intend to end the year of 2013 with cash and investments in the neighborhood of $210 million to $220 million. Importantly, cash into runway of 2015, and importantly, that runway allows us to have readouts, meaningful readouts in catalyst on the upcoming trials that we're planning, which include the beginning -- the 5 cohort expansions, a readout on those trials. We have submitted abstract to ASCO, but intend to have even a mature data set by ASH later this year. We intend to define the recommended Phase II dose, which will support registrational studies, report additional data from our Phase I trial and patients with advanced hematologic malignancies, of course, later this year, and enroll at least 2 additional trials. In inflammation, it's to complete the asthma study, as well as initiate the rheumatoid arthritis study. For -- our pipeline extension is to conduct the preclinical activities to enable Phase I initiation for IPI-443.
And for retaspimycin hydrochloride, we have actually 2 trials going on. I described the combination with docetaxel. We have another exploratory trial in combination with everolimus. So this is going to be a very busy year for us indeed. And if we look at our pipeline and developing pipeline, at the beginning of 2013, by the end of 2013, we should have data on the expansion cohorts, which are already enrolling. We anticipate, as I've said, 2 additional trials, Phase II trials. Data in asthma will be available for topline data, substantial enrollment in the rheumatoid arthritis trial, the completion of the 443 data and the 2 trials in lung cancer. Again, given this quite healthy series of events in 2013, 2013 is about execution and well into 2014, where we will get more meaningful data readouts as time goes on.
So that concludes my formal comments, and I welcome questions, and I think we also have a breakout session in Poinsettia 2, but I'll take any quick questions if there are any.
Thank you, Julian. So I guess we'll move to Poinsettia 2 for breakout. It's on this level to your right. Thank you.
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