Concerns on UCB/Immunomedics’ Phase III lupus trials

UCB and Immunomedics (NASDAQ: IMMU) expect top-line data from two Phase III trials (EMBODY 1 and EMBODY 2) of epratuzumab in 2015H1. Immunomedics’ fate hangs on the EMBODY trials, but the Phase IIb results that supported the EMBODY trials were not really all that good.

In May 2006, Immunomedics licensed epratuzumab to UCB for the treatment of non-cancer indications. Under the Amendment Agreement in December 2011, Immunomedics is entitled to receive up to $425 million in milestone payments and royalties ranging from 15-25% of net sales.

Epratuzumab is a humanized monoclonal antibody targets CD22, an antigen found on the surface of B cells. UCB is currently testing epratuzumab in systemic lupus erythematosus (SLE), an autoimmune disease affecting about one in 1,000 people.

GlaxoSmithKline’s anti-BAFF monoclonal antibody belimumab is the first new SLE drug in 50 years. The drug is only marginally effective and generated sales of £173 million in 2014. There is ample room for epratuzumab to take share.

In the Phase IIb trial (EMBLEM), SLE patients treated with 600 mg weekly of epratuzumab reported a 45.9% response rate compared with a 21.1% response rate for patients treated with placebo. The data[1] look pretty good, but there is no correlation between dose and response.

Placebo 100 mg

Q2W

400 mg

Q2W

600 mg

weekly

1200 mg

Q2W

1800 mg

Q2W

n 38 39 37 35 37 39
Responders 21.1% 30.8% 26.3% 45.9% 40.5% 23.7%
Serious AEs 7.9% 5.1% 5.4% 8.6% 10.8% 5.1%
Discontinuations 5.3% 15.4% 15.8% 21.6% 8.1% 7.9%

Analyst Avik Roy of Monness Crespi Hardt suggested:

Typically, an active drug generates more responses as the dose goes up. In trials where the response goes down as the dose goes up, the positive signal is usually the product of statistical noise, rather than of a true biological effect.

UCB and Immunomedics’ scientists just said that the mechanisms responsible for the low response rate seen with the highest tested dose require further investigation. In December 2010, UCB launched the EMBODY trials to assess the efficacy and safety of 600 mg weekly and 1200 mg Q2W regimens.

A second concern is that 21.6% of patients in the 600 mg weekly group discontinued the study compared to 5.3% from placebo. Dropouts may increase the risk of overall trial failure.

[1] Ann Rheum Dis. 2014, 73(1), 183-190.

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2 thoughts on “Concerns on UCB/Immunomedics’ Phase III lupus trials

  1. earl 2015-03-23 / 03:16

    The lack of dose related response in the Phase 2 trial had been part of the bearish argument against emab for quite awhile, until a study was published in Blood citing trogocytosis as the apparent method of action, which can be impeded at higher doses of drug.

    M. Goldenberg, Rosana Michel, Diane L. Rossi, Daniel J. Wallace and
    epratuzumab
    Trogocytosis of multiple B-cell surface markers by CD22 targeting with epratuzumab

    bloodjournal.hematologylibrary.org

    “In chronic lymphocytic leukemia, high doses of rituximab resulted
    in removal of rituximab-CD20 complexes by trogocytosis to monocytes,
    enabling these malignant cells to escape the effects of the
    antibody by antigenic modulation.13 Reducing the dose limited the
    extent of trogocytosis and improved the therapeutic effects.42 Based
    on our present findings, a similar process of antigen modulation via
    trogocytosis induced by anti-CD22 or anti-CD20 antibodies that
    extends beyond the respective targeted antigens can be implicated in
    their therapeutic efficacy. Although the effective dose of epratuzumab
    (ex vivo) spans from 10 ng/mL to 100 mg/mL with little difference in
    the extent of trogocytosis, higher concentrations resulted in diminished
    trogocytosis, which could result from FcgR blocking, instead
    of effector-target cell cross-linking. Further, the presence of excess
    epratuzumab may favor monovalent antigen binding, reduced antigen
    clustering, and limited translocation of CD22 to lipid rafts,36 all
    of which could limit trogocytosis. This could also explain the
    clinical observations that higher doses (720 mg/m2 weekly 3 4) of
    epratuzumab administered to SLE patients5,7 or lymphoma patients2
    did not show an improvement over the midrange dose (360 mg/m2
    weekly 3 4) used, because the serum concentration of .150 mg/mL
    may reduce trogocytosis efficiency.”

    Liked by 1 person

  2. earl 2015-03-23 / 03:54

    this section on MOA should have posted first:

    Blood Oct 2013

    “The present findings disclose a previously unknown, and potentially
    important,MOA of epratuzumab, which may be pertinent to its
    therapeutic effects in B-cell regulated autoimmune diseases. Based on
    these findings, the activity of epratuzumab on B cells is twofold, one
    via binding to CD22,which also occurs with F(ab9)2, and the other via
    engagement of FcgR-bearing effector cells. Whereas both epratuzumab
    and its F(ab9)2 fragment are capable of inducing internalization,
    as well as phosphorylation of CD22, with concurrent relocation to lipid rafts, only the former results in the trogocytosis of CD22 along
    with fellow BCR regulators including CD19, CD21, and CD79b, as
    well as the BCR itself, likely due to their close proximity to the
    epratuzumab-bound CD22. The pronounced (.90%) and persistent
    loss of CD22 on B cells by epratuzumab-mediated internalization and
    trogocytosis is expected to render B cells less active and less viable,
    and the accompanied decrease of CD19 could further enhance this
    effect.

    “We propose that epratuzumab-mediated loss of CD22 and CD19, and
    possibly other BCR modulators and cell-adhesion molecules, incapacitates
    B cells to render them unresponsive to activation by
    T-cell–dependent antigens, leading to therapeutic control in B-cell–
    mediated autoimmune diseases. Indeed, CD19, CD22, CD21, and
    CD79b each were significantly lower on B cells of epratuzumab treated,
    compared with treatment-na¨ive, SLE patients, as reported
    here for the first time.”

    Like

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