Integrated Clinical Trial Analyses Further Substantiate that Teprotumumab Significantly Improves Debilitating Effects of Thyr...
October 31 2019 - 10:00AM
Business Wire
Horizon Therapeutics plc (Nasdaq: HZNP) today announced
integrated, pooled efficacy data from the Phase 2 and Phase 3
clinical trials of teprotumumab for the treatment of active thyroid
eye disease (TED) compared to placebo. The results support prior
analyses of significant reductions in inflammation, proptosis (eye
bulging) and diplopia (double vision), as well as improvements in
quality of life (QoL). These data were presented at the 89th Annual
Meeting of the American Thyroid Association (ATA). This is the
first presentation of the pooled analyses and builds on the
individual positive results of the Phase 2 and Phase 3 clinical
studies.
Teprotumumab is an investigational medicine and its safety and
efficacy have not been established. The teprotumumab Biologics
License Application (BLA) was granted Priority Review by the U.S.
Food and Drug Administration (FDA) and if approved, teprotumumab
would be the first FDA-approved medicine for the treatment of
active TED. The Prescription Drug User Fee Act (PDUFA) goal date is
March 8, 2020.
“This is the largest placebo-controlled evaluation of active
thyroid eye disease to date and an important step towards better
understanding the devastating, vision-threatening effects of this
disease,” said George Kahaly, M.D., Ph.D., of the Johannes
Gutenberg University Medical Center in Mainz, Germany and lead
study author. “These data highlight the urgent need for targeted
intervention strategies and illustrate the potential for
teprotumumab to reduce the painful and disfiguring symptoms of
thyroid eye disease, and importantly, to help improve quality of
life.”
The pooled analysis of the Phase 2 (NCT01868997) and Phase 3
OPTIC (NCT03298867) studies presented during ATA represent the
experience of 171 patients with recent onset of TED (less than nine
months) treated with teprotumumab or placebo every three weeks for
a total of eight infusions.
Key study findings include the following:
- Proptosis: At Week 24, 77.4% of
patients receiving teprotumumab experienced a ≥2 mm reduction in
proptosis, compared to 14.9% of patients receiving placebo
(p<0.001). The reduction in average change from baseline through
Week 24 in proptosis was greater in patients who received
teprotumumab (-2.63 mm) than in those who received placebo (-0.31
mm, p<0.001).
- Diplopia: The diplopia responder
rate, which is defined as the percentage of patients whose diplopia
improved 1 or more grades, was higher with teprotumumab (69.7%)
versus placebo (30.5%; p<0.001) in those with baseline
diplopia.
- Quality of Life: Patients treated
with teprotumumab experienced improvements in average change from
baseline through week 24 in QoL scores (overall 15.55 vs 5.92,
p<0.001), including visual functioning (16.81 vs 6.10,
p<0.001) and appearance (13.51 vs 5.78, p=0.002). The GO-QoL
scale consists of two subscales to evaluate the quality of life of
patients with TED (Graves’ Ophthalmology), including impacts on
visual function and self-assessment of appearance. A change of 6
points is considered clinically significant.1
- Clinical Activity Score (CAS): At
Week 24, nearly two-thirds of teprotumumab-treated patients (61.9%)
had no or minimal inflammatory symptoms as measured by CAS
(described as a CAS of 0 or 1) compared to 21.8% of placebo-treated
patients (p<0.001). CAS is a scale used to assess the disease
activity of TED, and measures the degree of inflammation, including
pain, swelling and redness. The CAS scale ranges from 0 to 7, with
a score of 0 representing no signs or symptoms of
inflammation.2
- In addition, 73.8% of teprotumumab patients versus 13.8% of
placebo patients had an overall response at Week 24 – defined as
the percent of patients with ≥ 2-point reduction in CAS and ≥ 2 mm
reduction in proptosis from baseline.
As previously reported, the majority of adverse events
experienced with teprotumumab treatment were graded as mild to
moderate and were managed in the trials, with few discontinuations.
In the Phase 2 clinical study, the only drug-related adverse event
identified by the investigators was hyperglycemia. Other adverse
events included nausea, diarrhea, muscle spasms, hearing impairment
and inflammatory bowel disease in a patient with a recent diagnosis
of ileitis and colitis. No deaths occurred during the trial. The
safety profile of teprotumumab in the Phase 3 clinical study was
similar to that seen in the Phase 2 study with no new safety
observations.
“The combined integrated results of the Phase 2 and Phase 3
teprotumumab clinical trials demonstrate compelling data in a
disease state that is currently lacking therapies for the painful
symptoms, disfigurement and vision impairment that TED patients
endure,” said Shao-Lee Lin, M.D., Ph.D., executive vice president,
head of research and development and chief scientific officer,
Horizon. “We are excited by the positive effects demonstrated in
the areas that matter most to patients – proptosis, double vision
and quality of life – and we are excited about the potential
teprotumumab has to be the first FDA-approved treatment for thyroid
eye disease.”
About Thyroid Eye Disease
Thyroid eye disease (TED) is a serious, progressive and
vision-threatening autoimmune disease with a limited window of
activity that can last up to three years.3,4,5 While TED often
occurs in people living with hyperthyroidism or Graves’ disease, it
is a distinct disease that is caused by autoantibodies activating
an IGF-1R-mediated signaling complex on cells within the orbit.6,7
This leads to a cascade of negative effects, which may cause
long-term, irreversible damage. Active TED is characterized by
inflammation and tissue expansion behind the eye.3,8 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.4,9 TED
has only been shown to respond to pharmacotherapy while the disease
is active and inflammation is ongoing.10 Currently, patients must
live with active TED until the disease becomes inactive – often
left with permanent and vision-impairing consequences.3,8
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 has received Priority Review, Orphan Drug,
Fast Track and Breakthrough Therapy designations from the FDA. The
clinical development program for teprotumumab in the treatment of
TED includes positive results from the Phase 3 OPTIC confirmatory
clinical trial as well as positive Phase 2 results, which were
published in The New England Journal of Medicine. The OPTIC trial
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., Ph.D.,
Johannes Gutenberg University Medical Center. Horizon is also
conducting the OPTIC‐X extension trial to gather further insight
into the long-term efficacy and safety of teprotumumab.
About Horizon
Horizon is focused on researching, developing and
commercializing medicines that address critical needs for people
impacted by rare and rheumatic diseases. Our pipeline is
purposeful: we apply scientific expertise and courage to bring
clinically meaningful therapies to patients. We believe science and
compassion must work together to transform lives. For more
information on how we go to incredible lengths to impact lives,
please visit www.horizontherapeutics.com, follow us @HorizonNews 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 the potential regulatory approval of
teprotumumab and the potential benefits of teprotumumab as a
treatment for active TED. Forward-looking statements speak only as
of the date of this press release and Horizon 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 the FDA will approve teprotumumab as a treatment for active
TED, risks associated with clinical development of medicine
candidates and whether Horizon will be able to successfully
commercialize teprotumumab, if approved. For a further description
of these and other risks facing Horizon, please see the risk
factors described in Horizon'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 undertakes no obligation to update or revise
these statements, except as may be required by law.
References
- Terwee CB. Interpretation and Validity of Changes in Scores on
the Graves’ Ophthalmopathy Quality of Life Questionnaire (GO-QOL)
After Different Treatments. Clinical Endocrinology 2001; 54:
391-398.
- Wiersinga WM, Perros P, Kahaly GJ, et al. Clinical assessment
of patients with Graves’ orbitopathy: the European Group on Graves’
Orbitopathy recommendations to generalists, specialists and
clinical researchers. Eur J Endocrinol 2006; 155: 387-9.
- Barrio-Barrio J, et al. 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.
- Ross DS, et al. 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.
- Shan SJ, Douglas RS. The Pathophysiology of Thyroid Eye
Disease. Journal of Neuro-Ophthalmology. 2014; 34: 177-185.
- Bahn RS. Graves' Ophthalmopathy. The New England Journal of
Medicine. 25 February 2010.
https://www.nejm.org/doi/full/10.1056/NEJMra0905750. Accessed Feb
22, 2019.
- Pritchard J, et al. 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.
- Bothun ED, et al. 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.
- McKeag D, et al. 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.
- Mamoojee Y, Pearce SHS. Natural History. In: Wiersinga WM,
Kahaly GJ (eds): Graves’ Orbitopathy: A Multidisciplinary Approach
– Questions and Answers. Basel, Karger. 2017:93-104.
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