Innovation Pharmaceuticals Inc (IPIX)

[slcimmuno]

On the Roche Nutlin (RG7388, idasanutlin) -- yeah, def a competitor of Kevetrin, another MDM2 inhibitor in trials, including for AML (Bologna, one of the sites--so no surprise researchers there looking to test another MDM2-inhibitor like Kevetrin, the new kid on the block). But it has major toxicity, tolerance issues, just like the earlier Roche MDM2 antagonist (RG7112).

At bottom, the Roche Nutlin’s (RG7388) topline results for AML (ph I/Ib) presented in Dec 2014 at a Cancer conference -- the kind of detailed data we'll eventually see for Kevetrin Ph I at D Farber for solid tumors (am sure some of the more clinical folks here can help interpret the dosing regimen, efficacy data).

To the toxicity point, for the monotherapy arm, excerpt: "Further enrollment in this arm was discontinued as induction of prolonged myelosuppression increased the risks of infection and early deaths. Combination treatment with lower RG7388 doses may be better tolerated in this fragile elderly population."

Background on RG7388
http://www.biooncology.com/pipeline-molecules/idasanutlin-mdm2-antagonist
"Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development" (2013, abstract only)
http://www.ncbi.nlm.nih.gov/m/pubmed/23808545/

Does look like the lead Bologna-Kevetrin would be Giovanni Martinelli, per ROMAD Diver's research -- he’s listed in the second spot of Roche AML study. Alberto Martelli also perhaps a tie in given his bio, work on p53.

Martinelli (English translation)
https://translate.googleusercontent.com/translate_c?depth=1&nv=1&rurl=translate.google.com&sl=it&tl=en&u=http://www.unibo.it/SitoWebDocente/default.aspx%3FUPN%3Dgiovanni.martinelli2%2540unibo.it%26View%3DCV&usg=ALkJrhg6R7YpQ2aHMnkF8U12bE6pE3_nqQ

Martelli
http://www.unibo.it/Faculty/default.aspx?UPN=alberto.martelli%40unibo.it&View=CV
"Exploiting p53 Status to Enhance Effectiveness of Chemotherapy by Lowering Associated Toxicity" (2011) (Martelli et al)
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=247&path%5B%5D=371

Based on a scan of the clinical lit, seems Roche was hoping RG7388 would be more tolerable than RG7112, another mdm2 inhibitor, using intermittent scheduling......
"Preclinical optimization of mdm2 antagonist scheduling for cancer treatment by using a model-based approach" (May 2014)
http://clincancerres.aacrjournals.org/content/early/2014/05/08/1078-0432.CCR-14-0460.full.pdf
.......but, again, doesn't look like its panning out in the early human trials, again, as evidenced most recently by the Dec 2014 AML data release (the mono-arm discontinued)

Fair to say Roche will likely only (only be able to) position RG7388 as a conjugant (w/cytarabine, e.g., AML) given how harsh it was on patients as a stand-alone therapy. Kevetrin, given its safety profile (no real issues to date, one AE if i recall), has the potential to be a monotherapy (as Leo/Menon have stated), again, unlike the Roche Nutlins.

In summary, a quick comparison w/ Roches Nutlin RG7388 (by extension RG7112):

1) Kevetrin activates both wtp53 and mutp53 (Roche Nutlins only the former)...

2) Kevetrin, so far, has been shown to be safe and well-tolerated as a monotherapy and no reason to think this won’t continue (per Waverunner1 and muelch discussion from earlier today—I hew more to Wrunner’s opinion/targeted therapies not all panacea per Pazdur and other’s comments out of ASCO, have their own challenges as to safety/efficacy). (Roche Nutlins have not been well-tolerated across all trials they’ve initiated--blogger Derek Lowe described Nutlins as the "only-a-mother-could-love-it small molecule" given its ugly side-effects profile
http://pipeline.corante.com/archives/2015/01/20/a_new_cell_assay_and_what_it_says_about_stapled_peptides.php

3) Kevetrin also affects transcriptional-dependent and transcriptional-independent p53 pathways... Important in apoptosis (see study below) and another key distinction that I think (still researching this) separates it from other p53 drugs in development. (other feel free to chime in)
Study: "A Two-Step Mechanism for Cell Fate Decision by Coordination of Nuclear and Mitochondrial p53 Activities" (June 2012) EXCERPT Our work suggests that both the transcription-independent and -dependent p53 activities are indispensable for a reliable choice of cell fate and also provides clues to therapeutic manipulation of the p53 pathway in cancer treatment.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038164

So who knows*...

(*Though we're getting closer to finding out, for reals, per the 2015 ASCO poster: "Kevetrin can be a major inducer of apoptosis in many types of tumors independent of p53 mutation status.")
http://cellceutix.com/wp-content/uploads/2015/05/ASCO-2015-Poster-.-FINAL-1.pdf

…. But perhaps, just perhaps: Kevetrin will be the first drug to break the ribbon and win "The Amazing p53 Race"
http://seekingalpha.com/article/1121491-the-amazing-p53-race
…. And after that, in first position, Kevetrin will reign supreme as "the centripetal force for oncolytic compound conjugation"
http://seekingalpha.com/article/1473151

In other words, the last best word on Kevetrin might be--perhaps it is "the one".... The drug that finally cracks the p53 code, i.e., a whole lot of cancers finally having met their match, their killer. To borrow from F Baum and A Huxley, "Oh what a world, what a world -- a brave new world," that'd be.

To close, a quote from Dr. Kumar --- based on reading one of my re Kevetrin posts (link), which had been fwd'd to him:

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=114181026

KUMAR: "I am very pleased that people are taking time to understand why kevetrin is multimodal in function. It's very exciting time."

Exciting. Indeed.

///////

ROCHE NUTLIN RG7388 / AML

"Phase 1/1b Study of RG7388, a Potent MDM2 Antagonist, in Acute Myelogenous Leukemia (AML) Patients (Pts)" (Dec 2014)
https://ash.confex.com/ash/2014/webprogram/Paper69271.html

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: New Drugs I

Sunday, December 7, 2014: 4:45 PM
West Building, 2001-2003-2014-2016 (Moscone Center)
Karen Yee, MD1, Giovanni Martinelli, MD2, Norbert Vey, MD PhD3*, Michael J. Dickinson, MBBS, FRACP, FRCPA4, Karen Seiter, MD5, Sarit Assouline, MD, MSc6, Mark Drummond, MD, PhD7*, Sung-Soo Yoon, MD, PhD8, Margaret Kasner, M.D.9, Je-Hwan Lee, MD, PhD10, Kevin R. Kelly, MD, PhD11, Steven Blotner, PhD12*, Brian Higgins12*, Steven Middleton, PhD12*, Gwen Nichols, MD12, Gong Chen, PhD12*, Hua Zhong, PhD12*, William E. Pierceall, PhD12, Jianguo Zhi, PhD12* and Lin-Chi Chen, MD, PhD12
1Princess Margaret Hospital, Toronto, Canada
2Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
3Hematology, Institut Paoli Calmettes, Marseille, France
4Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
5New York Medical College, Valhalla, NY
6Division of Hematology, Jewish General Hospital, McGill University, Montreal, QC, Canada
7Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, Scotland
8Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
9Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
10Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
11Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX
12Roche Innovation Center New York, Roche Pharma Research & Early Development, New York, NY

Background: RG7388 is a new, potent, oral, nutlin-class MDM2 antagonist. This trial evaluated its use in AML to determine the recommended phase 2 dose (RP2D), dose-limiting toxicities (DLTs), pharmacokinetics (PK), pharmacodynamics and clinical responses.

Methods: This multicenter, open-label phase 1/1b dose escalation (DE) study evaluated RG7388 as monotherapy (daily ´ 5 d q28d) (Part 1 DE) and in combination with cytarabine (ara-C 1 g/m2 IV x 6 d q28d) (Part 2 DE). Extensions (Ex) were initiated at the RP2D. Part 1Ex (RG7388) included pts > 70 y or > 60 y with comorbidities. Part 2Ex pts (RG7388 ± ara-C) had relapsed/refractory (R/R) AML, = 2 regimens and no antecedent hematologic disorders (AHD) or transplant (ASCT). Blood and marrow analyses included PK, TP53mutations (mt) by AmpliChip, serum MIC-1 and MDM2gene expression.

Results: To date, 86 pts have been treated. DE is complete, Part 1Ex was discontinued after 9 pts and 34 of 40 planned pts are enrolled in Part 2Ex. One DLT of prolonged myelosuppression was reported. RP2D is 1200 mg/d (600 mg bid) x 5 d q28d for both mono- and combination therapy due to diarrhea not formally a DLT but felt to be dose-limiting. The most common adverse events were GI (diarrhea reported by > 85% of pts) or infection-related (> 70% of pts).

Twenty pts received monotherapy during Part 1 DE at 400 (n = 2), 800 (n = 6) and 1600 mg (n = 12) daily x 5 d. Median age was 68.5 y (range 28-83 y), median prior therapies = 2 (range 0-4), 1 pt had ASCT and 8 had AHD. Four pts died in the first 30 days. Five pts achieved either a CR (n = 2) or CRi/MLFS (n = 3).

In Part 1Ex, 9 pts were treated with RG7388 at the RP2D. Median age was 75 y (range 66-83), 8 pts had AHD (6 prior hypomethylators, 3 pts lower intensity therapy) and 1 had prior solid tumor. Best responses reported were 1 CRi/MLFS, 1 PR, 1HI, 3 PD. Three pts died in the first 30 days. Further enrollment in this arm was discontinued as induction of prolonged myelosuppression increased the risks of infection and early deaths. Combination treatment with lower RG7388 doses may be better tolerated in this fragile elderly population.

Twenty-three pts were enrolled in Part 2 DE (RG7388 + ara-C) at daily doses of 400 (n = 10), 800 (n = 7), and 1200 mg (n = 6); median age 64 y (range 32-76); median prior therapies = 1.5 (range 0-5); prior ASCT 2; AHD 4; 5 had prior malignancies. Four pts died in the first 30 days. Six relapsed AML pts achieved CRs (4 received prior ara-C and 2 had prior hypomethylators).

To date, 34 of 40 planned pts with R/R AML have been enrolled to Part 2Ex (RG7388 ± ara-C); 23 pts have responses reported, with 4 CRs, 1 CRi, 1 PR, 1 HI, 16 PD. Three pts died in the first 30 days. T1/2 is ˜ 1 d, irrespective of age, concomitant azoles or ara-C. Bone marrow levels are ˜ 70% of plasma drug levels at steady state. CRs were seen in diverse pts, including varied risk groups, prior AHD, therapy-related AML (t-AML), p53 mt, R/R and de novo AML. All pts who achieved a CR during DE were relapse free for > 60 d. One pt on monotherapy and 2 on combination therapy remained relapse free for > 400 d and > 200 d from start of study, respectively. A potential predictive gene expression signature correlated with RG7388 therapy (AUC = 0.73, p = 0.021).

Conclusions: We report the Ph1/1b PK, safety and clinical activity of a new, potent MDM2 antagonist in AML. CRs occur rapidly and are durable (> 60 d) in elderly AML pts with RG7388 monotherapy and in R/R pts with combination therapy.

Patient characteristics by response to treatment

Part 1 DE (N = 20) 16 responses
Best response 2 CR; 3CRi/MLFS 3 PR 4 HI 4 PD
TP53 status WT WT 1 MT, 3 WT 1 V
ELN*
AHD(responders) 4 I, 1 A
3 (MDS, MF, CMML) 3 I
2 (MDS, CMML)
Part 1Ex (N = 9) 6 responses
Best response 1 CRi/MLFS 0 PR 2 HI 3 PD
TP53 status WT WT, MT 2 WT, 1 U
ELN*
AHD(responders) I
ET

Part 2 DE (N = 23) 20 responses
Best response 6 CR 2 PR
2 HI 10 PD

TP53 status 1 MT WT WT 1 MT, 1 V
ELN*
AHD(responders) 1 F, 3 I, 2 A
1 t-AML 1 I, 1 A
Part 2Ex (N = 34) 23 responses
Best response 4 CR; 1 CRi/MLFS 1 PR 1 HI 16 PD
TP53 status 4 WT, 1 U WT WT 1 MT, 5 WT, 10 U
ELN*(responders) 1 F, 3 I, 1 A A
CR, complete remission; CRi, complete remission with incomplete recovery; HI, hematologic improvement; MLFS, morphologic leukemia-free state; PD, progressive disease; PR, partial response; WT, wild type; V, splice variant; U, unknown/pending; AHD, includes myelodysplastic syndrome (MDS), essential thrombocythemia (ET), chronic myelomonocytic leukemia (CMML), myelofibrosis(MF)
*ELN: Risk by European Leukemia Net: favorable (F), Intermediate I and II (I), or adverse (A)

Disclosures: Yee: Roche: Research Funding. Martinelli: Pfizer:Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ARIAD:Consultancy, Speakers Bureau. Vey: Roche: Honoraria. Assouline:Roche: Honoraria, Research Funding; Janssen: Honoraria. Drummond: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Blotner:Roche: Employment. Higgins: Roche: Employment. Middleton:Roche: Employment. Nichols: Roche: Employment. Chen: Roche:Employment. Zhong: Roche: Employment. Pierceall: Roche:Employment. Zhi: Roche: Employment. Chen: Roche: Employment.