AbbVie Inc. (ABBV) Earnings Call Transcript & Summary

Hello, my name is James Purcell. I'm an employee at AbbVie. And I'm going to be speaking today about targeting PTK7 with the antibody drug conjugate, ABBV-647, which was formerly known as PF-06647020. Thank you to the conference organizers for putting this great event together. A lot of excellent speakers and talkers, and I'm sure this will be a great session. Thank you. So here are my disclosures. PTK7 is a member of the noncanonical Wnt signaling pathway. And as shown here on the right is the PTK7 signaling. It is a transmembrane receptor that has multiple roles in embryonic development as well as tissue homeostasis. On a cellular level, PTK7 also has additional roles in cell movement, migration, as well as invasion. It has been shown to interact with ligand's co-receptors and transfusion of the Wnt signaling pathway, suggesting a role in fine-tuning of this actual network. However, the exact downstream processes are not fully elucidated. So this is signaling through junk to [ Cejon ] activation. And when we think about the Wnt signaling pathway, we more typically think about the classical beta-catenin beta pathway, which is shown here on this next slide. Let me just turn on the pointer here. So you can see here, this is the classical Wnt signaling pathway with, say, Wnt3, leading to beta-catenin activation translocation to the nucleus, and then ultimately, driving transcription of target genes. The PTK7 is a little less clear, but the dose seem to be some potential crosstalk between these 2 pathways. And interestingly, it is not your typical receptor kinase, and it does not have a functional kinase domain. Therefore, it is believed to function primarily via its interactions with both extra and intracellular binding partners. So this is, I guess, some additional data that further created additional information in terms of the function of PTK7. So PTK7 knockout mice, quite striking here that there's clearly a functional impact of removing this gene on the embryonic development. Clearly, these mice have severe polarity defects as well as neural tube closure issues. Again, emphasizing the role that this target plays in development, cell polarity, et cetera. So our interest from a cancer perspective as an ADC target, in large part, is based around not only its expression profile, but also some biology observations that I will show and give additional information on shortly. So when we look at its expression in normal tissue, this is RNA-seq in a large tissue data set called GTEx. You can see that in general, there is lower expression of PTK7 in a lot of normal tissues. There definitely is some normal tissue expression. However, when we look in the cancer setting, you can see that in general, there is much higher expression in the cancer tumor indications than what we see in this normal tissue, and this is on a [ log 2 ] scale. And some of the indications that I've highlighted here include lung adeno, squamous, ovarian and breast cancer. And these are indications that were part of the Phase I trial, which I'll be discussing a little bit later on. But this is the sort of characteristics we look for when thinking about what might make a good ADC target, higher cancer expression than normal expression and some sort of tumor normal differential. As I said, there definitely is some normal tissue expression. And some I'd see here to confirm what those tissues were and these include esophagus, bladder, some epithelial kidney expression, mammary gland, lung and also stromal expression in a number of tissues. And this is something that we've also seen in the cancer setting, where there is some stromal fibroblast expression in certain cancer settings as well. But by and large, the vast majority of major tissues in organs are either negative or very low for expression of PTK7. So this target originally became of interest at a company called Stemcentrx, which was subsequently acquired by AbbVie. And Stemcentrx, their model was around understanding and learning more about tumor-initiating cells or cancer stem cells. And their approach was to source patient-derived xenografts that have been generated from human cancer biopsies, looking at heterogeneity, positive and negative populations to see which are more tumor genic and have a greater tumor potential. So using this approach, I'm using some of the markers that they use to identify these tumor-initiating cells. They split PTK7 positive and negative populations in a number of a PDX models. What's shown here on the left is [ OV555 ], an ovarian PDX. And when the positive or negative cells were implanted into mice, you can see that only the PTK7 positive implanted cells, those mice actually developed tumors, whereas PTK7 negative cells did not result in tumor at growth. And this was seen in a number of different models below, as an example, in a lung PDX model. And additional information is shown here in this table on the right. And a lot of this data was published by Marc Damelin and also speaking in this session. So really nice publication and a lot of interesting biology and coverage as part of this work. And this was ultimately what led to a collaboration between Stemcentrx and Pfizer. And moving forward then of this as a target of interest, going after a target that seems to have the ability to target these more tumorgenic type cancer cells. And this observation as it relates to PTK7 function as a kind of stem-type marker was also seen and reported in the literature. This is an example from a colon-based paper where they looked at PTK7 negative low or high from primary stem cells. And you can see in culture that, again, these PTK7 high are much more proliferative and better ability to form organize. And similarly, when we think about the cells that are most important for that stem characteristic and ultimately, colorectal cancer development are the cells in the base of the crypt. And of these [ VLI ], where we have PTK7 expression. Again, taking out these types of populations and doing flow sorting, you can see again that the PTK7 high cells are the more proliferative cancer cells or more proliferative cells, I should say. So this data ultimately resulted in a collaboration, as I said, with Pfizer. They had their own auristatin-based linker drug, auristatin-101. It is a [ Maleimide Val-Cit ]. So cleavable drug linker. And in many regards, has a lot of similarities to MMAE as it relates to structure, mechanism and potency. Stemcentrx has developed their own PTK7 antibody, 6M24, which was a wild-type IgG1. And the ADC that was generated was using standard melamine-based conjugation with broad dashboard distribution, ranging from 0 to 8. So here is some of the efficacy data that was seen with this particular ADC and a number of these PDX models. Robust anti-tumor regressions and cures were seen in quite a number of models. And this is at a 3 mg per kg dose level, dosed q4d x4. And you can see superiority to standard-of-care chemo, dosed at a clinically relevant dose in terms of dose level and tolerability. This is 20 mg per kg for docetaxel or 5 mg per kg for cisplatin. And interestingly, when tumors were treated with the ADC and compared to, say, standard-of-care agent like docetaxel, the frequency of these tumor-initiating cells will seem to decrease again, fitting with hypothesis that PTK7 is expressed on these more tumorgenic proliferative type cells. The nonclinical safety profile shows no target-dependent toxicity. In large regards, it was very much MTI auristatin-based platform findings such as reversible myelosuppression. This was seen in both monkeys and rats. Some additional findings included lymphoid depletion, testicular findings and increased mitosis, all of which are commonly seen with a payload mechanism such as what has seen in ABBV-647. And overall, as I said, safety profile, very similar to other proteolytic capable [ MCVC-based ] ADCs, such as MMAE. And in terms of tolerability in the species, rash, HNSD listed as 6 mg per kg and monkey listed as 4 mg per kg, which allowed them to define their MRSD dose for the clinical dose escalation of 0.2 mg per kg based on 1/6 HNSD. So this drug then moved into a Phase I dose-escalation study run by Pfizer, starting at 0.2 mg per kg and escalated as high as 3.7 with the expansion cohorts moving forward at the 2.8 mg per kg on a q3-week schedule. There were 3 distinct patient populations evaluated in dose expansion, triple-negative breast cancer, non-small cell lung and ovarian cancer. Of note, the ovarian cancer population was not selected in terms of PTK expression. There was some selection incorporated into the non-small cell lung and triple-negative breast cancer, looking for moderate-to-high expression. And there was also an evaluation on a 2-week schedule to see if modifying the Ctrough and the exposures could ultimately change some of the safety and activity profile. This has not been published yet, but will be at a later date by our Pfizer colleagues. So I will be focusing on the Phase I observations, that's q3-week dosing schedule. So the Phase I patient baseline characteristics. This was very much a heavily pretreated population. The mean was listed here in this red box in terms of prior lines of therapy. So the average was 4 prior lines of therapy across all these indications. But in each cohort, there was some patients that haven't received as many as 12 or even 15 prior lines of therapy. So very heavily pretreated patient population. Here's the pharmacokinetic profile. The PK exposure is increased in a dose-dependent manner between the 0.2 to 3.7 mg per kg dose level. At the 2.8 mg per kg expansion cohort dose, the half-life was approximately 3 days. And you can see that there is a nice correlation between total antibody and ADC exposures with a ratio of 0.9 in terms of ADC indicating that there was a reasonable linker drug stability at the antibody and ADC were seen intact. Here is the summary of the safety observations. In terms of findings, it was very much in line with what has been seen with other microtubule inhibitor ADCs. There was no evidence of on-target toxicity. And Grade 3, 4 neutropenia was the most clinical relevant AE that was observed. Dose-limiting toxicities, there was 2, one Grade 3 headache, one Grade 3 fatigue. And this was seen at the 3.7 mg per kg cohort. And there was encouragingly also low rates of neuropathy observed as opposed to many other MTI ADCs where neuropathy can be a clinical challenge. For this particular agent, neuropathy was still seen, but the grade was generally low and manageable which is certainly encouraging. Here is the efficacy summary. And the table shows the triple negative, non-small cell lung and ovarian cancer efficacy that was observed in these patients. The ORR was 21% for triple-negative breast cancer with a median duration response of 4.3 months, with the longest duration of response that was observed being 10.2 months. In non-small cell lung cancer, above 2.1 mg per kg, the response rate was 17% with a median duration of response of close to 6 months, which in this patient population is actually quite encouraging. And some patients staying on treatment for as long as 10 months. In ovarian cancer, this was the largest cohort of patients, 44 patients. There was a 27% objective response rate, mean duration of response being 4.2 months, with some patients staying on study as long as 8.3 months. As you can see from the waterfall plots, the ovarian population. Clearly, there is a nice group of patients that are responding to this drug. Keep in mind, this was not a patient population that was selected based on PTK7. So this is all-comer ovarian. There was also one complete response, which is very encouraging for a drug in this heavily pretreated relapsed/refractory setting. In non-small cell lung cancer, above 2.1 mg per kg, there was a number of PRs. And again, showing that there was good activity for this agent in this particular setting. So the patient that had the complete response in ovarian cancer, this was a 52-year-old woman with advanced ovarian cancer, so Sirius [indiscernible] form. She had 4-plus prior lines of therapy, including [indiscernible] carbo-liposomal dox and now paclitaxel. And you can see at baseline, a very large lesion here. After 2 cycles, this has then become a PR based on RECIST. And following 4 cycles, tumor had completely disappeared. And this was certainly an encouraging and highly responsive patient to this drug. So right now, the focus for this drug is actually primarily non-small cell lung cancer. And part of the reason for that is based on data that was published as it relates to expression and response. And this was published at AACR. In the ovarian responder population, the mean H score was 111. However, the nonresponder population was 80. So it didn't necessarily seem like there are a way to enrich for these responders in this setting. In non-small cell lung, the responders had a mean H score of 200, nonresponder is a little bit lower, suggesting that there was a potential for some enrichment. And similarly, in triple-negative breast cancer, there was also a trend for higher H score in the responders than the nonresponders. So some of the reasons for moving forward in non-small cell lung cancer was evidence of PTK7 high efficacy enrichment, a viable patient PTK7 positive population. So enough patients that we believe have the level of PTK7 expression needed to get good response, and high unmet medical need and attractive landscape options as well. So right now, there is an active Phase Ib efficacy and safety study, that is ongoing in recurrent non-small cell lung cancer. And this is in patients that have received prior platinum chemotherapy doublet as well as immune checkpoint inhibitors. The dose that was selected was 2.8 mg per kg q3-week, so matching was shown earlier. And there is patient selection for PTK7 high tumors by IC to maximize patient response and durability. And the exact IC cut point is an active part of research to determine what that appropriate IHC level should be. So with that, I'll conclude by thanking all of the investigators, study sponsor, patient families who participated in this Phase I trial that was run by Pfizer, and all of the ongoing patients as part of the ongoing AbbVie-Pfizer Phase Ib trial. Also would like to thank all the study staff and project teams for their many contributions across both organizations. So with that, I'll conclude. Thank you for your attention, and happy to follow-up online with the Q&A session. Thank you.