ABBV/PCYC: Imbruvica and ABT-199 are Synergistic

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Richard Evans / Scott Hinds / Ryan Baum

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@SSRHealth

April 15, 2015

ABBV/PCYC: Imbruvica and ABT-199 are Synergistic

  • ABBV’s acquisition of PCYC raised eyebrows, both because of the valuation placed on PCYC, and because ABBV has a promising lead compound (ABT-199) being developed for the same B-cell malignancies treated by PCYC’s main product (Imbruvica)
  • Much debate centers on which is better – Imbruvica or ABT-199. We think this misses the point; the drugs are far more likely to be used together than in lieu of one another
  • Imbruvica is a leap forward in the treatment of B-cell malignancies, but complete responses are rare, and patients have shown resistance. Malignant B-cells adapt to Imbruvica by altering the shape of Imbruvica’s target, altering the shape of the protein cleaved by Imbruvica’s target, and/or relying on alternative mechanisms to carry out the functions of the pathway blocked by Imbruvica. Imbruvica needs a partner
  • At least six teams of investigators have shown that Imbruvica and ABT-199 in combination are synergistic, and/or that ABT-199 remains effective even after cells develop resistance to Imbruvica. At least two teams of investigators have analyzed multiple potential partners for Imbruvica, and both have identified ABT-199 as the best choice
  • The evidence that Imbruvica and ABT-199 are synergistic sheds important light on the ABBV/PCYC transaction. Treatment of B-cell malignancies is plainly going to be multi-modal. Owning just one of the promising components of the multi-modal treatment doesn’t guarantee commercial success – witness the jockeying among antivirals for inclusion in the standard of care for HIV and HCV, and the reality that highly effective components failed to be included in the prevailing standard(s)
  • Conversely, owning the first two ‘dominant’ components of multi-modal B-cell therapy makes it far more likely that ABBV plays a controlling role in developing and commercializing the multi-modal standard of care for B-cell malignancies

Where we’re BULLISH: Biopharma companies with undervalued pipelines (e.g. VRTX, BMY, SNY, ROCHE); Biopharma companies with pending major product approvals (e.g. ALIOF, ALKS, AMGN, BDSI, EBS, ENDP, HLUYY, HSP, ICPT, JAZZ, NVS, PTCT, RLYP, RPRX, TSRO, UCBJY, UTHR, VRTX); ABBV and ENTA on sales prospects in Hep C; SNY on undervalued basal insulin franchise and sales potential for Praluent (alirocumab), in addition to its undervalued pipeline; AZN and LLY on the likelihood that excess SG&A/R&D spending must be reined in, in addition to pending major product approvals; CFN, BCR, CNMD and TFX on rising hospital patient volumes; XRAY and PDCO on rising dental patient volumes and rising average dollar values of dental products and services consumed per visit; CNC, MOH and WCG on bullish prospects for Medicaid HMOs; and, DVA and FMS for the likely gross margin effects of generic forms of Epogen

Where we’re BEARISH: Biopharma companies with overvalued pipelines (e.g. GILD, ALXN, SHPG, REGN, CELG, NVO, BIIB); PBMs facing loss of generic dispensing margin as the AWP pricing benchmark is replaced (e.g. ESRX, CTRX); Drug Retail as dispensing margins are pressured by narrowing retail networks and replacement of AWP (e.g. WBA, CVS, RAD); Research Tools & Services companies as growth expectations and valuations are too high in an environment of falling biopharma R&D spend (e.g. CRL, Q, ICLR); and, suppliers of capital equipment to hospitals on the likelihood hospitals over-invested in capital equipment before the roll-out of the Affordable Care Act (e.g. ISRG, EKTAY, HAE)

A quick grounding in normal and abnormal B-cell behavior

B-cells are the (incredibly specific) smart bombs of the immune system. Each is capable of binding and aiding in the elimination of but one very specific target. If and when the target appears the B-cells specific to that target proliferate in vast quantities and aid in that target’s elimination; and, once the target is dealt with the involved B-cells simply die. Normal B-cells have four jobs: wait, proliferate, bind (and call for help), and die

B-cells learn which of these jobs to do by sensing their microenvironment, largely through the B-cell receptor (BCR) pathway. Cancerous B-cells tend to use this pathway and its signals inappropriately – rather than waiting (and not multiplying) or simply dying, cancerous B-cells manage to proliferate and survive for extended periods

Imbruvica needs a partner

Imbruvica (ibrutinib) blocks signals that would otherwise travel down the BCR pathway by blocking one of several enzymes (Bruton’s tyrosine kinase, or ‘BTK’) that serves to carry signals from the cell’s exterior to the cell’s interior. Ibrutinib is highly effective in B-cell malignancies; however responses to ibrutinib are typically partial rather than complete; and, some patients have developed resistance. One of two proven means of developing resistance to ibrutinib is for the gene encoding BTK to mutate, subtly changing the BTK enzyme’s structure so that ibrutinib binds BTK less strongly (ibrutinib binds ‘normal’ BTK irreversibly), allowing the mutated BTK to function even in the presence of ibrutinib. The second proven means of cells becoming resistant to ibrutinib involves changes in the protein[1] that is acted on by BTK[2],[3]

Cancerous B-cells also tend to over-express other proteins that regulate B-cell activity, but that operate outside of the BCR pathway – in particular B-cell lymphoma 2, or ‘BCL-2’. At least some cancerous B-cells that are resistant to various forms of treatment express more BCL-2 than resistant cells[4], and it appears likely that some resistant cells use an up-regulated BCL-2 to compensate for a blocked BCR. BCL-2 is the molecular target of ABBV’s developmental drug ABT-199

Because complete responses to ibrutinib are rare, and because the development of resistance is relatively common, it is highly likely that therapies hoping to rein-in malignant B-cells’ tendencies to proliferate and survive will have to be multi-modal – i.e. ibrutinib needs one or more partners. This is very familiar territory. Most cancer regimens include multiple agents, and simultaneous use of multiple agents to attack proteins that mutate and/or cell processes that adapt is state of the art for treatment of both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections

ABT-199 is an inherently logical candidate for partner, and is supported by extensive evidence

Because BCR (and within it BTK, the target of ibrutinib) and BCL-2 (ABT-199’s target) are functionally intertwined, combination therapy with ibrutinib and ABT-199 has an inherent logic. This leaves the questions of whether ABT-199 is synergistic[5] with ibrutinib, whether ABT-199 works when ibrutinib fails; and whether ABT-199 is the best of several potential partners for ibrutinib

At least six groups of investigators have studied combinations of ibrutinib with other therapies involved in B-cell regulation, both inside and outside the BCR pathway, and in so doing have shown that ABT-199 and ibrutinib are in fact synergistic; and, that ABT-199 remains effective in cells that are resistant to ibrutinib. And, two of the investigator groups evaluated ABT-199 against multiple other agents for synergy with ibrutinib, and in both cases ABT-199 was a more suitable partner for ibrutinib than any of the other agents tested

  • Axelrod et al[6] evaluated ibrutinib in combination with 14 other agents[7] in two Mantle cell lymphoma (MCL) cell lines. ABT-199 demonstrated greater, and more consistent, synergy with ibrutinib than any of the other agents tested. These investigators subsequently confirmed these results in MCL and chronic lymphocytic leukemia (CLL) patient samples[8]
  • Cervantes-Gomez[9] et al also evaluated multiple agents[10] for synergy with ibrutinib, in cell cultures from 15 CLL patients. The ibrutinib / ABT-199 combination was the most effective of those tested, and results indicate the two drugs in combination are synergistic (p=0.05 for non-stimulated and p=0.0002 for IgM stimulated cell cultures)
  • Cao et al studied the effect of adding ABT-199 to either ibrutinib or idelalisib (Zydelig) in WM cell cultures. The authors found evidence of synergy at nearly all dose combinations evaluated[11]
  • Zhao et al evaluated the combination of ibrutinib and ABT-199 in multiple mantle cell lymphoma (MCL) lines, and found synergistic efficacy in all lines tested[12],[13]
  • Kuo et al[14] evaluated BCL-2 and spleen tyrosine kinase (SYK) inhibitors in combination with ibrutinib in ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL) cell lines. The authors found that ABT-199 was effective in these ibrutinib resistant cells (ABT-199 was not ranked relative to the other BCL-2 or SYK inhibitors). A high prevalence of BCL-2 mutations was found in the ibrutinib resistant lines, however none of the mutations involved the ABT-199 binding domains
  • Chitta et al have shown that ABT-199’s target (BCL-2) is up-regulated in WM cells that are resistant to either ibrutinib or bortezomib (Velcade), that these cells are nevertheless sensitive to ABT-199; and, that treatment of these resistant cells with ABT-199 appears to at least partially reverse these cells’ resistance to ibrutinib and bortezomib[15]
  1. Phospholipase C gamma 2
  2. Woyach, JA, et al.; “Resistance Mechanisms for the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib” N Engl J Med 370;24, pp 2286-2294
  3. Furman, RR, et al.; “Ibrutinib Resistance in Chronic Lymphocytic Leukemia; Letter to the Editor” N Engl J Med 370;24, 2352-2354
  4. Ibid 15
  5. Meaning the rate of cell death in cultures exceeded the rate that would have been expected based on rates observed with either ABT-199 or ibrutinib alone
  6. Axelrod, M, et al, “Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma”, Leukemia (2014) 404-463
  7. ABT-199, bendamustine, carfilzomib, bortezomib, geldanamycin, panobinostat, SC514, PD325901, PD0332991, enzastaurin, R788, temsirolimus, dasatinib, and idelalisib
  8. Portell, CA et al, “Synergistic cytotoxicity of ibrutinib and the BCL-2 antagonist ABT-199 in MCL and CLL: Molecular analysis reveals mechanisms of target interactions”, Abstract 509, 56th ASH Annual Meeting
  9. Cervantes-Gomez et al., “Pharmacological and protein profiling suggest venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia”, manuscript peer-reviewed and accepted for publication; accessed at clincancerres.aacrjournals.org
  10. ABT-199, ABT-737, idelalisib, and bendamustine
  11. Cao, Y. et al, “The BCL-2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXRCR4wild-type and CXCR4whim mutated Waldenstrom macroglobulinemia cells” British Journal of Haematology, doi: 10.1111/bjh.13278
  12. Zhao X, et al, “Combination of ibrutinib with ABT-199, a BCL-2 pathway inhibitor: Effective therapeutic strategy in a novel mantle cell lymphoma cell line model”, Blood; http://www.bloodjournal.org/content/122/21/645
  13. Zhao X, et al, “Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT, and BCL2 pathways”, British Journal of Haematology, 2015, 168, 757-768
  14. Kuo et al, “Combination of ibrutinib and BCL-2 or SYK inhibitors in ibrutinib resistant ABC-subtype of diffuse large B-cell lymphoma”, Abstract 505, 56th ASH Annual Meeting
  15. Chitta, KS, et al, “The Selective BCL-2 inhibitor ABT-199 synergizes with BTK or proteasome inhibitors to induce potent cell death in preclinical models of bortezomib or ibrutinib-resistant Waldenstrom’s Macroglobulinemia”, Abstract 1689, 56th ASH Annual Meeting
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