REG - Hutchmed China Ltd - U.S. FDA Approval of FRUZAQLA™ (fruquintinib)

HUTCHMED (China)Announcement

09/11/2023 07:15

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RNS Number : 9238S  Hutchmed (China) Limited  09 November 2023

HUTCHMED Announces that Takeda Receives U.S. FDA Approval of FRUZAQLA™ (fruquintinib) for Previously Treated Metastatic Colorectal Cancer

 

- FRUZAQLA is the first targeted therapy approved in the U.S. for metastatic
colorectal cancer regardless of biomarker status or prior types of therapies
in more than a decade -

 

- U.S. approval of FRUZAQLA triggers first milestone payment from Takeda of
US$35 million and royalties on net sales -

 

Hong Kong, Shanghai & Florham Park, NJ - Thursday, November 9, 2023:
HUTCHMED (China) Limited (Nasdaq/AIM: HCM, HKEX: 13) ("HUTCHMED
(https://www.hutch-med.com/) ") today announced that its partner Takeda
received approval from the U.S. Food and Drug Administration ("FDA") for
FRUZAQLA™ (fruquintinib), an oral targeted therapy for adults with
metastatic colorectal cancer ("CRC") who have been previously treated with
fluoropyrimidine-, oxaliplatin‑, and irinotecan‑based chemotherapy, an
anti‑vascular endothelial growth factor ("VEGF") therapy, and, if RAS
wild‑type and medically appropriate, an anti-epidermal growth factor
receptor (EGFR) therapy. FRUZAQLA is the first and only selective inhibitor of
all three VEGF receptor kinases approved in the U.S. for previously treated
metastatic CRC regardless of biomarker status.(1,2) This approval was received
under Priority Review more than 20 days ahead of the scheduled Prescription
Drug Users Fee Act (PDUFA) date of November 30, 2023.

 

"This is a landmark moment for metastatic colorectal cancer patients in the
U.S., who will soon have a much-needed new treatment option that improves
survival rates without negatively impacting their quality of life," said
Weiguo Su, PhD, Chief Executive Officer and Chief Scientific Officer of
HUTCHMED. "It is also a landmark moment for HUTCHMED, as we see our first
medicine approved outside of our home market, where we have been improving
patient outcomes with our novel oncology medicines for the last 5 years. In
late 2022 we launched a partnership strategy for globalizing our innovative
drug candidates and we are pleased to see early delivery of this new approach
just a year later. This initial success is thanks to our partner Takeda, who
saw the value in fruquintinib, shared our vision for taking it global, and
worked hard with us to secure U.S. approval. We look forward to continuing our
work with Takeda in an effort to bring FRUZAQLA to patients across the globe."

 

Takeda has the exclusive worldwide license
(https://www.hutch-med.com/closing-of-fruquintinib-license-to-takeda-outside-china/)
to further develop, commercialize, and manufacture fruquintinib outside of
mainland China, Hong Kong and Macau. The FDA approval of FRUZAQLA triggers a
US$35 million milestone payment from Takeda. HUTCHMED will receive royalties
on net sales, and is also eligible to receive potential payments relating to
other regulatory, development and commercial sales milestones. Fruquintinib is
developed and marketed in China by HUTCHMED following approval in September
2018, under the brand name ELUNATE™, in partnership with Eli Lilly and
Company.

 

"For more than a decade there has been limited innovation for patients with
metastatic colorectal cancer, one of the leading causes of cancer death in the
U.S.," said Teresa Bitetti, President of the Global Oncology Business Unit at
Takeda. "We are proud that our partnership with HUTCHMED enabled us to bring
forth a new option to this patient population and we look forward to
continuing our work for patients with this underserved cancer."

 

The approval of FRUZAQLA is based on data from two large Phase III trials: the
multi-regional FRESCO-2 trial, data from which were published
(https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/fulltext)
in The Lancet, along with the FRESCO trial conducted in China, data from which
were published (https://jamanetwork.com/journals/jama/fullarticle/2685988) in
JAMA, The Journal of the American Medical Association. The trials investigated
FRUZAQLA plus best supportive care versus placebo plus best supportive care in
patients with previously treated mCRC. Both FRESCO and FRESCO-2 met their
primary and key secondary efficacy endpoints and showed consistent benefit
among a total of 734 patients treated with FRUZAQLA. Safety profiles were
consistent across trials.

 

"Metastatic colorectal cancer patients often present with inoperable disease.
As cancer care providers, we must evaluate and consider treatment options that
will improve overall survival without compromising quality of life," said
Cathy Eng, M.D., FACP, at Vanderbilt University Medical Center. "A selective
oral anti-VEGF agent with proven benefit in overall survival and demonstrated
a manageable safety profile would be advantageous for patients by continuing
the treatment paradigm of anti-VEGF therapy at home."

 

In the U.S., approximately 153,000 new cases of CRC will be diagnosed in 2023,
representing 7.8% of all new cancer cases.(3,4) Approximately 70% of patients
with CRC will experience metastatic disease, whether at diagnosis or after
treatment. Metastases are the main cause of CRC-related mortality.(5,6)

 

The data from FRESCO and FRESCO-2 also supported the marketing authorization
application ("MAA") for fruquintinib, which was validated and accepted for
review by the European Medicines Agency ("EMA") in June 2023
(https://www.takedaoncology.com/news/news-releases/takeda-and-hutchmed-announce-marketing-authorization-application-of-fruquintinib/)
. A submission to the Japan Pharmaceuticals and Medical Devices Agency
("PMDA") also took place in September 2023
(https://www.takedaoncology.com/news/news-releases/takeda-submits-new-drug-application-for-fruquintinib-for-previously-treated-metastatic-colorectal-cancer-in-japan/)
.

 

About FRUZAQLA (fruquintinib)

FRUZAQLA (fruquintinib) is a selective oral inhibitor of VEGFR -1, -2 and -3.
VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. FRUZAQLA
was designed to have enhanced selectivity that limits off-target kinase
activity, allowing for high drug exposure, sustained target inhibition, and
flexibility for the potential use as part of combination therapy. FRUZAQLA has
demonstrated a manageable safety profile and is being investigated in
combinations with other anti-cancer therapies.

 

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS

·    Hypertension occurred in 49% of 911 patients with mCRC treated with
FRUZAQLA, including Grade 3-4 events in 19%, and hypertensive crisis in three
patients (0.3%). Do not initiate FRUZAQLA unless blood pressure is adequately
controlled. Monitor blood pressure weekly for the first month and at least
monthly thereafter as clinically indicated. Initiate or adjust
anti-hypertensive therapy as appropriate. Withhold, reduce dose, or
permanently discontinue FRUZAQLA based on severity of hypertension.

·    Hemorrhagic Events including serious, fatal events can occur with
FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 6% of patients
experienced gastrointestinal hemorrhage, including 1% with a Grade ≥3 event
and 2 patients with fatal hemorrhages. Permanently discontinue FRUZAQLA in
patients with severe or life-threatening hemorrhage. Monitor the International
Normalized Ratio (INR) levels in patients receiving anticoagulants.

·    Infections. FRUZAQLA can increase the risk of infections, including
fatal infections. In 911 patients with mCRC treated with FRUZAQLA, the most
common infections were urinary tract infections (6.8%), upper respiratory
tract infections (3.2%) and pneumonia (2.5%); fatal infections included
pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory
tract infection (0.1%), and septic shock (0.1%). Withhold FRUZAQLA for Grade 3
or 4 infections, or worsening infection of any grade. Resume FRUZAQLA at the
same dose when the infection has resolved.

·    Gastrointestinal Perforation occurred in patients treated with
FRUZAQLA. In 911 patients with mCRC treated with FRUZAQLA, 1.3% experienced a
Grade ≥3 gastrointestinal perforation, including one fatal event.
Permanently discontinue FRUZAQLA in patients who develop gastrointestinal
perforation or fistula.

·    Hepatotoxicity. FRUZAQLA can cause liver injury. In 911 patients with
mCRC treated with FRUZAQLA, 48% experienced increased ALT or AST, including
Grade ≥3 events in 5%, and fatal events in 0.2% of patients. Monitor liver
function tests (ALT, AST, and bilirubin) before initiation and periodically
throughout treatment with FRUZAQLA. Temporarily hold and then reduce or
permanently discontinue FRUZAQLA depending on the severity and persistence of
hepatotoxicity as manifested by elevated liver function tests.

·    Proteinuria. FRUZAQLA can cause proteinuria. In 911 patients with
mCRC treated with FRUZAQLA, 36% experienced proteinuria and 2.5% of patients
experienced Grade ≥3 events. Monitor for proteinuria before initiation and
periodically throughout treatment with FRUZAQLA. For proteinuria
≥2g/24 hours, withhold FRUZAQLA until improvement to ≤Grade 1
proteinuria and resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in
patients who develop nephrotic syndrome.

·    Palmar-Plantar Erythrodysesthesia (PPE) occurred in 35% of 911
patients treated with FRUZAQLA, including 8% with Grade 3 events. Based on
severity of PPE, withhold FRUZAQLA and then resume at the same or reduced
dose.

·    Posterior Reversible Encephalopathy Syndrome (PRES), a syndrome of
subcortical vasogenic edema diagnosed by characteristic finding on MRI,
occurred in one of 911 patients treated with FRUZAQLA. Perform an evaluation
for PRES in any patient presenting with seizures, headache, visual
disturbances, confusion, or altered mental function. Discontinue FRUZAQLA in
patients who develop PRES.

·    Impaired Wound Healing. In 911 patients with mCRC treated with
FRUZAQLA, 1 patient experienced a Grade 2 event of wound dehiscence. Do not
administer FRUZAQLA for at least 2 weeks prior to major surgery. Do not
administer FRUZAQLA for at least 2 weeks after major surgery and until
adequate wound healing. The safety of resumption of FRUZAQLA after resolution
of wound healing complications has not been established.

·    Arterial Thromboembolic Events. In 911 patients with mCRC treated
with FRUZAQLA, 0.8% of patients experienced an arterial thromboembolic event.
Initiation of FRUZAQLA in patients with a recent history of thromboembolic
events should be carefully considered. In patients who develop arterial
thromboembolism, discontinue FRUZAQLA.

·    Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6
(Sunset Yellow FCF). FRUZAQLA 1 mg capsules contain FD&C Yellow No. 5
(tartrazine), which may cause allergic-type reactions (including bronchial
asthma) in certain susceptible persons. FRUZAQLA 1 mg contains FD&C
Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions.

·    Embryo-Fetal Toxicity. Based on findings in animal studies and its
mechanism of action, FRUZAQLA can cause fetal harm when administered to
pregnant women. Advise pregnant women of the potential risk to a fetus. Advise
females of childbearing potential and males with female partners of
childbearing potential to use effective contraception during treatment with
FRUZAQLA and for 2 weeks after the last dose.

 

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) following treatment with
FRUZAQLA included hypertension, palmar-plantar erythrodysesthesia (hand-foot
skin reactions), proteinuria, dysphonia, abdominal pain, diarrhea, and
asthenia.

 

DRUG INTERACTIONS: Avoid concomitant administration of FRUZAQLA with strong or
moderate CYP3A inducers.

 

USE IN SPECIFIC POPULATIONS

·    Lactation: Advise women not to breastfeed during treatment with
FRUZAQLA and for 2 weeks after the last dose.

 

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at
1-844-662-8532 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
(https://www.fda.gov/medwatch) .

 

Please see FRUZAQLA (fruquintinib) full Prescribing Information
https://takeda.info/Fruzaqla-Prescribing-Information
(https://takeda.info/Fruzaqla-Prescribing-Information) .

 

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the
International Agency for Research on Cancer, CRC is the third most prevalent
cancer worldwide, associated with more than 935,000 deaths in 2020.(7) In the
U.S., it is estimated that 153,000 patients will be diagnosed with CRC and
53,000 deaths from the disease will occur in 2023.(3) In Europe, CRC was the
second most common cancer in 2020, with approximately 520,000 new cases and
245,000 deaths. In Japan, CRC was the most common cancer, with an estimated
148,000 new cases and 60,000 deaths in 2020.(7) Although early-stage CRC can
be surgically resected, metastatic CRC remains an area of high unmet need with
poor outcomes and limited treatment options. Some patients with metastatic CRC
may benefit from personalized therapeutic strategies based on molecular
characteristics; however, most patients have tumors that do not harbor
actionable mutations.(8,9,10,11,12)

 

About the Phase III FRESCO-2 Trial

The FRESCO-2 study is a multi-regional clinical trial conducted in the U.S.,
Europe, Japan and Australia investigating FRUZAQLA (fruquintinib) plus best
supportive care vs placebo plus best supportive care in patients with
previously treated metastatic CRC (NCT04322539
(https://clinicaltrials.gov/ct2/show/NCT04322539) ). The study met its primary
and key secondary endpoints, demonstrating that treatment with FRUZAQLA
resulted in statistically significant and clinically meaningful improvement in
overall survival (OS) and progression-free survival (PFS). The safety profile
of FRUZAQLA in FRESCO-2 was consistent with previously reported FRUZAQLA
studies. Results from the study were presented
(https://www.hutch-med.com/fruquintinib-fresco-2-data-summary-esmo-2022/) at
the European Society for Medical Oncology (ESMO) Congress in September 2022
and subsequently published
(https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00772-9/fulltext)
in The Lancet.(13,14)

 

The Phase III FRESCO and FRESCO-2 trials supported the MAA from the EMA for
fruquintinib, which was validated and accepted for review in June 2023. A
submission to the PMDA also took place in September 2023.

 

About HUTCHMED

HUTCHMED (Nasdaq/AIM:HCM; HKEX:13) is an innovative, commercial-stage,
biopharmaceutical company. It is committed to the discovery and global
development and commercialization of targeted therapies and immunotherapies
for the treatment of cancer and immunological diseases. It has approximately
5,000 personnel across all its companies, at the center of which is a team of
about 1,800 in oncology/immunology. Since inception it has focused on bringing
cancer drug candidates from in-house discovery to patients around the world,
with its first three oncology drugs now approved and marketed in China. For
more information, please visit: www.hutch-med.com (http://www.hutch-med.com/)
or follow us on LinkedIn (https://www.linkedin.com/company/hutchmed/) .

 

Forward-Looking Statements

This announcement contains forward-looking statements within the meaning of
the "safe harbor" provisions of the U.S. Private Securities Litigation Reform
Act of 1995. These forward-looking statements reflect HUTCHMED's current
expectations regarding future events, including its expectations regarding the
approval of a NDA for fruquintinib for the treatment of CRC with the EMA and
the PMDA and the timing of such approvals, the therapeutic potential of
fruquintinib for the treatment of patients with CRC and the further clinical
development of fruquintinib in this and other indications. Forward-looking
statements involve risks and uncertainties. Such risks and uncertainties
include, among other things, assumptions regarding the timing and outcome of
clinical studies and the sufficiency of clinical data to support NDA approval
of fruquintinib for the treatment of patients with CRC or other indications in
the E.U., Japan or other jurisdictions, its potential to gain approvals from
regulatory authorities on an expedited basis or at all; the efficacy and
safety profile of fruquintinib; HUTCHMED and/or Takeda's ability to fund,
implement and complete its further clinical development and commercialization
plans for fruquintinib; the timing of these events; each party's ability to
satisfy the terms and conditions under the license agreement; actions of
regulatory agencies, which may affect the initiation, timing and progress of
clinical trials or the regulatory pathway for fruquintinib; Takeda's ability
to successfully develop, manufacture and commercialize fruquintinib; and the
impact of COVID-19 on general economic, regulatory and political conditions.
In addition, as certain studies rely on the use of other drug products such as
paclitaxel as combination therapeutics with fruquintinib, such risks and
uncertainties include assumptions regarding the safety, efficacy, supply and
continued regulatory approval of these therapeutics. Such forward-looking
statements include, without limitation, statements regarding the plan to
develop, manufacture and commercialize fruquintinib under the license
agreement; potential payments under the license agreement, including any
milestone or royalty payments; potential benefits of the license agreement;
and HUTCHMED's strategy, goals and anticipated milestones, business plans and
focus. Existing and prospective investors are cautioned not to place undue
reliance on these forward-looking statements, which speak only as of the date
hereof. For further discussion of these and other risks, see HUTCHMED's
filings with the U.S. Securities and Exchange Commission, on AIM and on The
Stock Exchange of Hong Kong Limited. HUTCHMED undertakes no obligation to
update or revise the information contained in this announcement, whether as a
result of new information, future events or circumstances or otherwise.

 

Medical Information

This announcement contains information about products that may not be
available in all countries, or may be available under different trademarks,
for different indications, in different dosages, or in different strengths.
Nothing contained herein should be considered a solicitation, promotion or
advertisement for any prescription drugs including the ones under development.

 

Inside Information

This announcement contains inside information for the purposes of Article 7 of
Regulation (EU) No 596/2014 (as it forms part of retained EU law as defined in
the European Union (Withdrawal) Act 2018).

 

CONTACTS
 Investor Enquiries                                                +852 2121 8200 / +1 973 306 4490 / ir@hutch-med.com
                                                                   (mailto:ir@hutch-med.com)

 Media Enquiries
 Ben Atwell / Alex Shaw, FTI Consulting                            +44 20 3727 1030 / +44 7771 913 902 (Mobile) /
                                                                   +44 7779 545 055 (Mobile) / HUTCHMED@fticonsulting.com
                                                                   (mailto:HUTCHMED@fticonsulting.com)
 Zhou Yi, Brunswick                                                +852 9783 6894 (Mobile) / HUTCHMED@brunswickgroup.com
                                                                   (mailto:HUTCHMED@brunswickgroup.com)
 Nominated Advisor
 Atholl Tweedie / Freddy Crossley / Daphne Zhang, Panmure Gordon   +44 (20) 7886 2500

 

References

1.     Xu X, et al. Efficacy and safety of regorafenib and fruquintinib as
third-line treatment for colorectal cancer: a narrative review. Transl Cancer
Res 2022;11(1):276-287. doi: 10.21037/tcr-20-3539.

2.     Sun Q, et al. (2014) Discovery of fruquintinib, a potent and highly
selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for
cancer therapy, Cancer Biol Ther. 2014 15:12, 1635-1645. doi:
10.4161/15384047.2014.964087.

3.     Siegel RL, et al. Colorectal cancer statistics, 2023 [published
online ahead of print, 2023 Mar 1]. CA Cancer J Clin. 2023; 73(3):233-254.
doi:10.3322/caac.21772.

4.     National Cancer Institute. Available at:
https://seer.cancer.gov/statfacts/html/colorect.html (accessed May 2023).

5.     Atreya CE, Yaeger R, Chu E. Systemic therapy for metastatic
colorectal cancer: from current standards to future molecular targeted
approaches. Am Soc Clin Oncol Educ Book. 2017;37:246-256.
doi:10.1200/EDBK_175679.

6.     Vatandoust S, et al. Colorectal cancer: Metastases to a single
organ. World J Gastroenterol. 2015;21(41):11767-76.
doi:10.3748/wjg.v21.i41.11767.

7.     Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021;71(3):209-249. doi:10.3322/caac.21660.

8.     Bando H, et al. Therapeutic landscape and future direction of
metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 2023;
20(5)306-322. doi:10.1038/s41575-022-00736-1.

9.     D'Haene N, et al. Clinical application of targeted next-generation
sequencing for colorectal cancer patients: a multicentric Belgian experience.
Oncotarget. 2018;9(29):20761-20768. Published 2018 Apr 17.
doi:10.18632/oncotarget.25099.

10.   Venderbosch, et al. Mismatch repair status and braf mutation status in
metastatic colorectal cancer patients: A pooled analysis of the Cairo, Cairo2,
coin, and Focus Studies. Clinical Cancer Res.,2014; 20(20):5322-5330.
doi:10.1158/1078-0432.ccr-14-0332.

11.   Koopman, M., et al. Deficient mismatch repair system in patients with
sporadic advanced colorectal cancer. Br J Cancer. 209;100(2), 266-273.
doi:10.1038/sj.bjc.6604867.

12.   Ahcene Djaballah S, et al. HER2 in Colorectal Cancer: The Long and
Winding Road From Negative Predictive Factor to Positive Actionable Target. Am
Soc Clin Oncol Educ Book. 2022;42:1-14. doi:10.1200/EDBK_351354.

13.   Dasari NA, et al. LBA25 - FRESCO-2: A global phase 3 multiregional
clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in
patients with refractory metastatic colorectal cancer. Ann Oncol. 2022
Sep;33(suppl_7): S1391-S1392. doi:10.1016/j.annonc.2022.08.021.

14.   Dasari NA, et al. Fruquintinib versus placebo in patients with
refractory metastatic colorectal cancer (FRESCO-2): an international,
multicentre, randomised, double-blind, phase 3 study [published online ahead
of print, 2023 Jun 15]. Lancet. 2023. doi: 10.1016/S0140-6736(23)00772-9.

 

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