Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints

Horizon Pharma plc (Nasdaq: HZNP) today announced topline results from
its Phase 3 confirmatory trial evaluating teprotumumab for the treatment
of active thyroid eye disease (TED). The study met its primary endpoint,
showing more patients treated with teprotumumab compared with placebo
had a meaningful improvement in proptosis, or bulging of the eye: 82.9
percent of teprotumumab patients compared to 9.5 percent of placebo
patients achieved the primary endpoint of a 2 mm or more reduction in
proptosis (p<0.001). Proptosis is the main cause of morbidity in TED.
All secondary endpoints were also met and the safety profile was
consistent with the Phase 2 study of teprotumumab in TED.

Horizon expects to submit a Biologics License Application to the U.S.
Food and Drug Administration (FDA) in mid-2019. Teprotumumab has
received Breakthrough Therapy, Orphan Drug and Fast Track designations
from the FDA. Detailed Phase 3 data will be submitted for publication in
a peer-reviewed journal and presented at a medical congress later this
year.

“The dramatic results of the teprotumumab Phase 3 confirmatory trial, in
addition to positive Phase 2 data, form a highly convincing body of
clinical evidence supporting teprotumumab for the treatment of active
thyroid eye disease,” said Timothy P. Walbert, chairman, president and
chief executive officer, Horizon Pharma plc. “This is a key milestone as
we evolve into a research-focused company developing innovative new
medicines to address challenging diseases with very few effective
options. We are one step closer to delivering the first FDA-approved
treatment to people living with active thyroid eye disease, and we are
grateful to the patients, physicians and investigational sites who have
partnered with Horizon to make the teprotumumab research and development
program possible.”

“In the study, patients treated with teprotumumab had an unprecedented
reduction in proptosis, which is currently only treatable via surgery
after the active disease has ended,” said Raymond Douglas, M.D., Ph.D.,
the study’s co-principal investigator and director of the orbital and
thyroid eye disease program, Cedars-Sinai Medical Center. “If approved,
teprotumumab would give physicians the first medicine shown to reduce
proptosis during active thyroid eye disease, in addition to treating
other painful symptoms.”

Highlights from the Phase 3 confirmatory trial, titled OPTIC (Treatment
of Graves’ Orbitopathy (Thyroid
Eye Disease) to Reduce Proptosis
with Teprotumumab Infusions
in a Randomized, Placebo-Controlled, Clinical
Study):

• Designed to investigate the efficacy, tolerability and safety of
  teprotumumab in patients with active TED.
• Eighty-three patients were assigned to receive teprotumumab or placebo
  in eight intravenous infusions (10mg/kg for their first infusion
  followed by 20mg/kg for the remaining seven infusions) every three
  weeks for 21 weeks.
• The primary endpoint was a responder rate of ≥ 2 mm reduction of
  proptosis in the study eye (without deterioration in the fellow eye)
  at Week 24.
• In the intent-to-treat population, 34/41 (82.9%) patients receiving
  teprotumumab and 4/42 (9.5%) patients receiving placebo were proptosis
  responders at Week 24 (p˂0.001).
• All secondary endpoints were also met (p≤0.001), which include the
  effect of teprotumumab vs. placebo on:
  • Overall responder rate at Week 24 (primary endpoint in the Phase 2
    study): Percent of participants with ≥2 point reduction in
    Clinical Activity Score (CAS) and ≥2 mm reduction in proptosis
    from baseline, provided there is no corresponding deterioration
    (≥2-point/mm increase) in CAS or proptosis in the fellow eye.
  • Percent of participants with a CAS value of 0 or 1 at Week 24 in
    the study eye.
  • Percent of patients with a change from baseline of at least one
    grade in diplopia (double vision).
  • Mean change in proptosis measurement from baseline to Week 24 in
    the study eye.
  • Mean change in Graves’ Ophthalmopathy Quality of Life from
    baseline to Week 24.
• The safety profile of teprotumumab in OPTIC was similar to that seen
  in the Phase 2 study with no new safety observations. The drop-out
  rate was low (<5%) and balanced across placebo and treatment arms.
  There were no deaths during the study and a total of three serious
  adverse events: in the placebo arm, one patient had a visual field
  defect and received orbital decompression surgery and discontinued
  study; in the teprotumumab arm, one patient had pneumothorax
  (considered not related to study drug) and another had an infusion
  reaction that led to discontinuation of study drug. The vast majority
  of treatment-emergent adverse events were mild to moderate in
  intensity and no other adverse events resulted in discontinuation.

TED is a progressive, debilitating autoimmune disease with a limited
window of active disease during which it can be treated without surgical
intervention.^1,2 While TED often occurs in people living with
hyperthyroidism or Graves’ disease, it is a distinct disease that is
caused by autoantigens activating an IGF-1R-mediated signaling complex
on cells within the orbit.^3,4 This leads to a cascade of
negative effects, which cause long-term, irreversible damage. Active TED
lasts for up to three years and is characterized by inflammation and
tissue expansion behind the eye.^5,1 As TED progresses, it
causes serious damage – including proptosis (eye bulging), strabismus
(misalignment of the eyes), and diplopia (double vision) – and in some
cases can lead to blindness.^2,6 Currently, patients must
suffer through active TED until the disease becomes inactive – often
left with permanent and sight-impairing consequences – before they can
have complex and costly surgical procedures that may never fully restore
vision or appearance.^5,1,7 People living with TED often
experience long-term functional, psychological and economic burdens,
including inability to work and perform activities of daily living.^7,8

Webcast

At 8 a.m. ET/1 p.m. IST today, the Company will host a live webcast to
discuss the results of the OPTIC trial and current treatment landscape
for TED. The live webcast and a replay may be accessed at http://ir.horizon-pharma.com.
Please connect to the Company's website at least 15 minutes prior to the
live webcast to ensure adequate time for any software download that may
be needed to access the webcast. A replay of the webcast will be
available approximately two hours after the live webcast.

About Teprotumumab

Teprotumumab is a fully human monoclonal antibody (mAb) and a targeted
inhibitor of the insulin-like growth factor 1 receptor (IGF-1R).
Teprotumumab is an investigational medicine and its safety and efficacy
have not been established. The Phase
3 OPTIC confirmatory clinical study was conducted at leading centers
in the U.S., Germany and Italy, with co-principal investigators Raymond
Douglas, M.D., Ph.D., Cedars-Sinai Medical Center; and George Kahaly,
M.D., Johannes Gutenberg University Medical Center. In addition to the
Phase 3 OPTIC trial, Horizon is conducting the OPTIC‐X
extension trial to gather further insight into the long-term
efficacy and safety of teprotumumab. The robust clinical development
program for teprotumumab in the treatment of TED includes positive Phase
2 results published in The
New England Journal of Medicine.

About Horizon Pharma plc

Horizon Pharma plc is focused on developing and commercializing
innovative medicines that address unmet treatment needs for rare
diseases, and rheumatic diseases, with a special interest for diseases
for which a deep understanding of immunology may lead to innovative ways
to control the disease. By fostering a growing pipeline of medicines in
development and through aggressive life cycle management of our
medicines, we strive to make a powerful difference for patients, their
caregivers and physicians. For us, it’s personal: by living up to our
own potential, we are helping others live up to theirs. For more
information, please visit www.horizonpharma.com,
follow us @HZNPplc
on Twitter, like us on Facebook
or explore career opportunities on LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements, including
statements regarding expectations regarding the submission of a BLA for
teprotumumab, expected publications and presentations of data from the
Phase 3 teprotumumab clinical trial, potential regulatory approval of
teprotumumab and the potential for teprotumumab as a treatment for TED.
Forward-looking statements speak only as of the date of this press
release and Horizon Pharma does not undertake any obligation to update
or revise these statements, except as may be required by law. These
forward-looking statements are based on management's expectations and
assumptions as of the date of this press release and actual results may
differ materially from those in these forward-looking statements as a
result of various factors. These factors include, but are not limited
to, risks regarding whether Horizon Pharma experiences delays in
submitting a BLA for teprotumumab, whether the FDA will accept the
planned BLA for filing or approve the BLA, risks associated with
clinical development of medicine candidates and whether Horizon Pharma
will be able to successfully commercialize teprotumumab, if approved.
For a further description of these and other risks facing Horizon
Pharma, please see the risk factors described in Horizon Pharma's
filings with the United States Securities and Exchange Commission,
including those factors discussed under the caption “Risk Factors” in
those filings. Forward-looking statements speak only as of the date of
this press release and Horizon Pharma undertakes no obligation to update
or revise these statements, except as may be required by law.

References

1. Graves’ Ophthalmopathy: VISA versus EUGOGO Classification, Assessment,
   and Management. Journal of Ophthalmology. 2015. https://www.hindawi.com/journals/joph/2015/249125/cta/.
   Accessed Feb 22, 2019.
2. The 2016 European Thyroid Association/European Group on Graves'
   Orbitopathy Guidelines for the Management of Graves' Orbitopathy. European
   Thyroid Journal. 2 March 2016. https://www.ncbi.nlm.nih.gov/pubmed/27099835.
   Accessed Feb 22, 2019.
3. Graves' Ophthalmopathy. The New England Journal of Medicine. 25
   February 2010. https://www.nejm.org/doi/full/10.1056/NEJMra0905750.
   Accessed Feb 22, 2019.
4. Igs from patients with Graves' disease induce the expression of T cell
   chemoattractants in their fibroblasts. The Journal of Immunology. 15
   January 2002. https://www.ncbi.nlm.nih.gov/pubmed/11777993.
   Accessed Feb 22, 2019.
5. Update on thyroid eye disease and management. Clinical
   Ophthalmology. 19 October 2009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2770865/.
   Accessed Feb 22, 2019.
6. Clinical features of dysthyroid optic neuropathy: a European Group on
   Graves' Orbitopathy (EUGOGO) survey. British Journal of
   Ophthalmology. 11 October 2006. https://www.ncbi.nlm.nih.gov/pubmed/17035276.
   Accessed Feb 22, 2019.
7. Quality of Life and Occupational Disability in Endocrine Orbitopathy. DA
   International. 24 April 2009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689575/.
   Accessed Feb 22, 2019.
8. Public health relevance of Graves' orbitopathy. The Journal of
   Clinical Endocrinology & Metabolism. 26 November 2012. https://www.ncbi.nlm.nih.gov/pubmed/23185037.
   Accessed Feb 22, 2019.

View source version on businesswire.com: https://www.businesswire.com/news/home/20190228005255/en/