Genentech’s HEMLIBRA (emicizumab-kxwh) Reduced Treated Bleeds by 96 Percent Compared to No Prophylaxis in Phase III HAVEN 3 Study in Hemophilia A without Factor VIII Inhibitors

– In a subset of patients in the HAVEN 3 study who previously received factor VIII prophylaxis, the standard of care, HEMLIBRA reduced bleeds by 68 percent compared to their prior therapy –

– Phase III HAVEN 4 results showed HEMLIBRA every four weeks provides clinically meaningful control of bleeding in people with or without factor VIII inhibitors –

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today full results from the Phase III HAVEN 3 study evaluating HEMLIBRA^® (emicizumab-kxwh) prophylaxis administered every week or every two weeks in people with hemophilia A without factor VIII inhibitors and the Phase III HAVEN 4 study evaluating HEMLIBRA prophylaxis administered every four weeks in people with hemophilia A with or without factor VIII inhibitors. Data from both pivotal studies were presented today as late-breaking abstracts at the World Federation of Hemophilia (WFH) 2018 World Congress in Glasgow, Scotland.

“HEMLIBRA is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrated by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” said Johnny Mahlangu, Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, South Africa. “Even with current prophylactic treatments, many people with hemophilia A continue to have bleeds that can lead to long-term joint damage, and there is a need for more treatment options.”

In the Phase III HAVEN 3 study, adults and adolescents aged 12 years or older without factor VIII inhibitors who received HEMLIBRA prophylaxis every week or every two weeks showed a 96 percent (p<0.0001) and 97 percent (p<0.0001) reduction in treated bleeds, respectively, compared to those who received no prophylaxis. In addition, 55.6 percent (95 percent CI: 38.1; 72.1) of people treated with HEMLIBRA every week and 60 percent (95 percent CI: 42.1; 76.1) of people treated with HEMLIBRA every two weeks experienced zero treated bleeds, compared to 0 percent (95 percent CI: 0.0; 18.5) of people treated with no prophylaxis. Importantly, in an intra-patient comparison, in people who were previously enrolled in a prospective non-interventional study (NIS), once-weekly HEMLIBRA prophylaxis showed superior efficacy compared to prior factor VIII prophylaxis, the standard of care for people with hemophilia A without factor VIII inhibitors, as demonstrated by a 68 percent reduction (p<0.0001) in treated bleeds. Additionally, 93.7 percent (n=89/95; 95 percent CI, 86.8; 97.7) of all participants who completed a treatment preference survey preferred HEMLIBRA to their previous hemophilia treatment, with 97.8 percent (n=45/46) of those in the intra-patient comparison preferring HEMLIBRA to their prior factor VIII prophylaxis. There were no unexpected or serious adverse events (AEs) related to HEMLIBRA, and the most common AEs were consistent with previous studies. The most common AEs occurring in 5 percent or more of people in the HAVEN 3 study were injection site reactions, joint pain (arthralgia), common cold symptoms (nasopharyngitis), headache, upper respiratory tract infection and influenza.

“These new pivotal data show that HEMLIBRA controlled bleeds in people with hemophilia A, while offering the flexibility of less frequent subcutaneous dosing options,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “With this data, we now have positive results from all four of our Phase III trials that reinforce the overall efficacy and safety of HEMLIBRA and its potential to improve care for all people with hemophilia A.”

In the single-arm Phase III HAVEN 4 study, adults and adolescents aged 12 years or older with or without factor VIII inhibitors receiving HEMLIBRA prophylaxis every four weeks had a median annualized bleeding rate (ABR) for treated bleeds of 0.0 (IQR: 0.0; 2.1), with 56.1 percent (95 percent CI: 39.7; 71.5) of people experiencing zero treated bleeds and 90.2 percent (95 percent CI: 76.9; 97.3) experiencing three or fewer treated bleeds. These results demonstrate that HEMLIBRA administration every four weeks can provide clinically meaningful control of bleeding in people with hemophilia A with or without factor VIII inhibitors. Additionally, all participants (n=41/41; 95 percent CI, 91.4; 100.0) who responded to a patient preference survey preferred HEMLIBRA to their previous hemophilia treatment. There were no serious AEs related to HEMLIBRA, and the most common AEs were consistent with previous studies. Injection site reaction was the most common AE, occurring in nine people in the HAVEN 4 study.

Separately, real-world data from the NIS on the impact of hemophilia A on health-related quality of life (HRQoL) and the burden of current treatment (either on-demand or prophylactic bypassing agents or factor VIII replacement therapy, depending on inhibitor status and local clinical guidelines) were also presented. Results from a cohort of the NIS in children with hemophilia A with factor VIII inhibitors showed that living with and managing the condition has a substantially negative impact on physical and emotional health and results in a significant burden for caregivers. In another cohort of the NIS, adults and adolescents with hemophilia A without factor VIII inhibitors reported higher HRQoL with prophylactic factor VIII treatment compared to episodic factor VIII treatment, based on validated tools including Haem-A-QoL and Haemo-QoL-SF. In addition, prophylactic factor VIII therapy resulted in fewer school and work days missed compared to episodic treatment. This NIS represents one of the largest studies of this type in people with hemophilia A with or without factor VIII inhibitors, and collected prospective real-world data for use as a valid historical control for pivotal studies in people with hemophilia A.

In April 2018, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to HEMLIBRA for people with hemophilia A without factor VIII inhibitors, based on data from the HAVEN 3 study. HEMLIBRA was approved by the FDA in November 2017 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors based on results from the HAVEN 1 study and interim results from the HAVEN 2 study. HEMLIBRA was also recently approved by regulatory authorities in other countries around the world, including by the European Commission in February 2018 for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Data from both the HAVEN 3 and HAVEN 4 studies are being submitted to health authorities around the world for approval consideration.

About HAVEN 3 (NCT02847637)

HAVEN 3 is a randomized, multicenter, open-label, Phase III study evaluating the efficacy, safety and pharmacokinetics of HEMLIBRA prophylaxis versus no prophylaxis (episodic/on-demand factor VIII treatment) in people with hemophilia A without factor VIII inhibitors. The study included 152 patients with hemophilia A (12 years of age or older) who were previously treated with factor VIII therapy either on-demand or for prophylaxis. Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive subcutaneous HEMLIBRA prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (Arm A), subcutaneous HEMLIBRA prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (Arm B), or no prophylaxis (Arm C). Patients previously treated with factor VIII prophylaxis received subcutaneous HEMLIBRA prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (Arm D). Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Study name	HAVEN 3 (NCT02847637)
Study group	No Prophylaxis (Arm C; n=18)	1.5 mg/kg HEMLIBRA Prophylaxis (Once weekly dosing) (Arm A; n=36)		3 mg/kg HEMLIBRA Prophylaxis (Dosing every two weeks) (Arm B; n=35)
Treated bleeds ABR (primary endpoint)
Median efficacy period, weeks (min-max)	24.0 (14.4-25.0)	29.6 (17.3-49.6)		31.3 (7.3-50.6)
Model-based ABR (95% CI)*	38.2 (22.9; 63.8)	1.5 (0.9; 2.5)		1.3 (0.8; 2.3)
% reduction vs arm C (RR, p-value)	N/A	96% reduction (0.04, p<0.0001)		97% reduction (0.03, p<0.0001)
Median ABR (Interquartile range; IQR)	40.4 (25.3; 56.7)	0.0 (0.0; 2.5)		0.0 (0.0; 1.9)
% patients with zero bleeds (95% CI)	0.0 (0.0; 18.5)	55.6 (38.1; 72.1)		60.0 (42.1; 76.1)
% patients with zero to three bleeds (95% CI)	5.6 (0.1; 27.3)	91.7 (77.5; 98.2)		94.3 (80.8; 99.3)
All bleeds (secondary endpoint)
Model-based ABR* (95% CI)	47.6 (28.5; 79.6)	2.5 (1.6; 3.9)		2.6 (1.6; 4.3)
% reduction RR^† (p-value)	N/A	95% reduction (p<0.0001)		94% reduction (p<0.0001)
% patients with zero bleeds (95% CI)	0.0 (0.0; 18.5)	50.0 (32.9; 67.1)		40.0 (23.9; 57.9)
Treated spontaneous bleeds (secondary endpoint)
Model-based ABR* (95% CI)	15.6 (7.6; 31.9)	1.0 (0.5; 1.9)		0.3 (0.1; 0.8)
% reduction RR^† (p-value)	N/A	94% reduction (p<0.0001)		98% reduction (p<0.0001)
% patients with 0 bleeds (95% CI)	22.2 (6.4; 47.6)	66.7 (49.0; 81.4)		88.6 (73.3; 96.8)
Treated joint bleeds (secondary endpoint)
Model-based ABR* (95% CI)	26.5 (14.7; 47.8)	1.1 (0.6; 1.9)		0.9 (0.4; 1.7)
% reduction RR^† (p-value)	N/A	96% reduction (p<0.0001)		97% reduction (p<0.0001)
% patients with 0 bleeds (95% CI)	0.0 (0.0; 18.5)	58.3 (40.8; 74.5)		74.3 (56.7; 87.5)
Treated target joint bleeds (secondary endpoint)
Model-based ABR* (95% CI)	13.0 (5.2; 32.3)	0.6 (0.3; 1.4)		0.7 (0.3; 1.6)
% reduction RR^† (p-value)	N/A	95% reduction (p<0.0001)		95% reduction (p<0.0001)
% patients with 0 bleeds (95% CI)	27.8 (9.7; 53.5)	69.4 (51.9; 83.7)		77.1 (59.9; 89.6)
Treated bleeds intra-patient comparison (Arm D patients who participated in NIS n=48; secondary endpoint)
Study group	Prior factor VIII prophylaxis (Arm C; n=48)		1.5 mg/kg HEMLIBRA Prophylaxis (Once weekly dosing) (Arm D; n=48)
Duration of efficacy period, median, (min-max), weeks	30.1 (5.0-45.1)		33.7 (20.1-48.6)
Model-based ABR* (95% CI)	4.8 (3.2; 7.1)		1.5 (1.0; 2.3)
% reduction vs NIS Factor VIII (RR, p-value)	68% reduction (0.32, p<0.0001)
Median ABR (IQR)	1.8 (0.0; 7.6)		0.0 (0.0; 2.1)
% patients with 0 bleeds (95% CI)	39.6 (25.8; 54.7)		54.2 (39.2; 68.6)
% patients with 0-3 bleeds (95% CI)	72.9 (58.2; 84.7)		91.7 (80.0; 97.7)

*Negative binomial regression model

^†Compared with Arm C

• Intra-patient comparison includes data from 48 patients in Arm D who participated in the NIS shown
• All arm D (n=63) ABR 1.6 (95% CI 1.1; 2.4); Percent zero bleeds 55.6 (95% CI 42.5; 68.1)

Haem-A-QoL Physical Health domain score
Study group	No Prophylaxis (Arm C; n=17)	1.5 mg/kg HEMLIBRA Prophylaxis (Once weekly dosing) (Arm A; n=36)	3 mg/kg HEMLIBRA Prophylaxis (Dosing every two weeks) (Arm B; n=35)
Physical Health domain score at Week 25
Patients, n	13	34	29
Adjusted mean difference (95% CI) vs Arm C	N/A	12.5 (–2.0; 27.0)	16.0 (1.2; 30.8)
P-value	N/A	0.089	0.035

• HEMLIBRA resulted in numerical improvement
• Since the comparison of Haem-A-QoL between Arms A and C is not statistically significant, the comparison of Arms B and C is not considered statistically significant due to the order of endpoints in the hierarchical testing framework

Haem-A-QoL: Haemophilia-Specific Quality of Life Questionnaire for Adults

HAVEN 3 Safety Summary: all HEMLIBRA participants HEMLIBRA prophylaxis (N=150)
n (%) unless otherwise stated	Arm A: 1.5 mg/kg QW (n = 36)	Arm B: 3 mg/kg Q2W (n = 35)	Arm C: 3 mg/kg Q2W (n = 16)	Arm D: 1.5 mg/kg QW (n = 63)	Total (N=150)
Total number of AEs	143	145	19	236	543
Selected serious AEs*	1	3	0	10	14
HEMLIBRA-related serious AEs	0	0	0	0	0
Selected AEs occurring in 5% or more of all patients, n (%)^‡
ISR^†	9 (25.0)	7 (20.0)	2 (12.5)	20 (31.7)	38 (25.3)
Upper respiratory tract infection	4 (11.1)	4 (11.4)	0	8 (12.7)	16 (10.7)
Patients with AE leading to withdrawal	0	1 (2.9)	0	0	1 (0.7)

Data represent period of HEMLIBRA prophylaxis only; at the clinical cutoff date, one patient was lost to follow-up and another was waiting to start HEMLIBRA

^† Grades 1–2 AE. 1 additional patient in Arm D (and total column) reported an “injection site erythema” not “injection site reaction” as the Preferred Term

^‡ Other AEs occurring in 5% of more of patients were arthralgia (19%), nasopharyngitis (12%), headache (11%), and influenza (6%)

• One patient in Arm B discontinued due to multiple mild AEs (insomnia, hair loss, nightmare, lethargy, depressed mood, headache and pruritus); two patients were lost to follow-up (Arms A and C, n=1 each)
• Of 215 events of co-exposure to factor VIII and HEMLIBRA in 64 patients, 43 included an average factor VIII dose ≥50 IU/kg/24 hours, of which 8 events lasted >24 hours; co-exposure to HEMLIBRA and factor VIII was not related to serious AEs, TMA or TEs
• No serious AE was associated with HEMLIBRA per investigator assessment
• No patients on HEMLIBRA developed de novo factor VIII inhibitors
• No ADAs detected

ADA, anti-drug antibodies; AE, adverse event; ISR, injection site reaction; NIS, non-interventional study; TE, thromboembolic event; TMA, thrombotic microangiopathy

About HAVEN 4 (NCT03020160)

HAVEN 4 is a single-arm, multicenter, open-label, Phase III study evaluating the efficacy, safety and pharmacokinetics (PK) of subcutaneous administration of HEMLIBRA dosed every four weeks. The study included 48 patients (12 years of age or older) with hemophilia A with or without factor VIII inhibitors who were previously treated with either factor VIII or bypassing agents, on-demand or as prophylaxis. The study was conducted in two parts: a PK run-in; and an expansion cohort. All patients in the PK run-in (n=7) were previously treated on-demand and received subcutaneous HEMLIBRA at 6 mg/kg to fully characterize the PK profile after a single dose during four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Patients in the expansion cohort (n=41) received subcutaneous HEMLIBRA prophylaxis at 3 mg/kg/wk for four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Episodic treatment of breakthrough bleeds with factor VIII therapy or bypassing agents, depending on a patient’s factor VIII inhibitor status, was allowed per study protocol.

Study name	HAVEN 4 (NCT03020160)
Study group	HEMLIBRA prophylaxis (n=48 total; n=41 included in efficacy analyses)
Treated bleeds
Annualized bleeding rate (ABR)*, model based (95% CI)	2.4 (1.4; 4.3)
Median ABR, calculated (IQR)	0.0 (0.0; 2.1)
% patients with zero bleeds (95% CI)	56.1 (39.7; 71.5)
% patients with zero to three bleeds (95% CI)	90.2 (76.9; 97.3)
All bleeds
ABR, model based (95% CI)	4.5 (3.1; 6.6)
Median ABR, calculated (IQR)	2.1 (0.0; 5.9)
% patients with zero bleeds (95% CI)	29.3 (16.1; 45.5)
% patients with zero to three bleeds (95% CI)	80.5 (65.1; 91.2)
Treated spontaneous bleeds
ABR, model based (95% CI)	0.6 (0.3; 1.5)
Median ABR, calculated (IQR)	0.0 (0.0; 0.0)
% patients with zero bleeds (95% CI)	82.9 (67.9; 92.8)
% patients with zero to three bleeds (95% CI)	97.6 (87.1; 99.9)
Treated joint bleeds
ABR, model based (95% CI)	1.7 (0.8; 3.7)
Median ABR, calculated (IQR)	0.0 (0.0; 1.9)
% patients with zero bleeds (95% CI)	70.7 (54.5; 83.9)
% patients with zero to three bleeds (95% CI)	95.1 (83.5; 99.4)
Treated target joint bleeds
ABR, model based (95% CI)	1.0 (0.3; 3.3)
Median ABR, Calculated (IQR)	0.0 (0.0; 0.0)
% patients with zero bleed (95% CI)	85.4 (70.8; 94.4)
% patients with zero to three bleeds (95% CI)	97.6 (87.1; 99.9)

*Negative binomial regression model

• Median (range) efficacy period, 25.6 (24.1-29.4) weeks
• Majority (38/51 [74.5%]) of treated bleeds were traumatic

Haem-A-QoL Physical Health domain score
	HEMLIBRA 6 mg/kg Q4W n=38*
	Baseline	Week 25
Patients	38	37
Physical Health domain score, mean (SD)	47.0 (25.1)	32.4 (25.4)
Change from baseline, mean (95% CI)	N/A	–15.1 (–22.4; –7.8)

• HEMLIBRA resulted in a numerical improvement
• Change from baseline in the Physical Health domain score for meaningful improvements: ≥10 points (responder threshold)
• *Analysis excludes adolescents (n=3)

HAVEN 4 Safety Summary
Total Number of AEs	148
Participants with ≥1 AE, n (%)	30 (73.2)
Serious AE, n (%) *	1 (2.4)
Grade ≥3 AE, n (%)	1 (2.4)
Related AE, n (%)	12 (29.3)
Local injection site reaction (ISR), n (%)	9 (22.0)
AESI
Hypersensitivity	0
TE/TMA	0

* One serious AE in the PK run-in cohort: grade 3 hypertension in patient with medical history of hypertension; unrelated to HEMLIBRA treatment.

• 73.2% of patients experienced ≥1 AE
• Only 1 serious (Grade ≥3) AE of rhabdomyolysis unrelated to HEMLIBRA
• Injection-site reaction was the most common HEMLIBRA-related AE (22.0%)
• No AEs led to HEMLIBRA discontinuation or withdrawal
• No TEs, TMAs or hypersensitivity reactions

PK, pharmacokinetics; SI, special interest

About HEMLIBRA

HEMLIBRA is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for hemophilia A patients. HEMLIBRA is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously) once weekly. HEMLIBRA was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche and Genentech.

HEMLIBRA U.S. Indication

HEMLIBRA is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors.

Important Safety Information

What is the most important information to know about HEMLIBRA?

HEMLIBRA increases the potential for blood to clot. Discontinue prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis. Carefully follow the healthcare provider’s instructions regarding when to use an on-demand bypassing agent, and the dose and schedule one should use. Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving HEMLIBRA prophylaxis.

HEMLIBRA may cause the following serious side effects when used with aPCC (FEIBA^®), including:

• Thrombotic microangiopathy (TMA). This is a condition involving blood clots and injury to small blood vessels that may cause harm to one’s kidneys, brain, and other organs. Patients should get medical help right away if they have any of the following signs or symptoms during or after treatment with HEMLIBRA:
  • confusion
  • weakness
  • swelling of arms and legs
  • yellowing of skin and eyes
  • stomach (abdomen) or back pain
  • nausea or vomiting
  • feeling sick
  • decreased urination
• Blood clots (thrombotic events). Blood clots may form in blood vessels in one’s arm, leg, lung or head. Patients should get medical help right away if they have any of these signs or symptoms of blood clots during or after treatment with HEMLIBRA:
  • swelling in arms or legs
  • pain or redness in the arms or legs
  • shortness of breath
  • chest pain or tightness
  • fast heart rate
  • cough up blood
  • feel faint
  • headache
  • numbness in the face
  • eye pain or swelling
  • trouble seeing

If aPCC (FEIBA^®) is needed, patients should talk to their healthcare provider in case they feel they need more than 100 U/kg of aPCC (FEIBA^®) total.

Before using HEMLIBRA, patients should tell their healthcare provider about all of their medical conditions, including if they:

• are pregnant or plan to become pregnant. It is not known if HEMLIBRA may harm an unborn baby. Females who are able to become pregnant should use birth control (contraception) during treatment with HEMLIBRA.
• are breastfeeding or plan to breastfeed. It is not known if HEMLIBRA passes into breast milk.

What should patients know about lab monitoring?

HEMLIBRA may interfere with laboratory tests that measure how well blood is clotting and may cause a false reading. Patients should talk to their healthcare provider about how this may affect their care.

The most common side effects of HEMLIBRA include: redness, tenderness, warmth, or itching at the site of injection; headache; and joint pain.

These are not all of the possible side effects of HEMLIBRA. Patients should call their doctor for medical advice about side effects.

Side effects may be reported to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch. Side effects may also be reported to Genentech at [phone].

Please see the HEMLIBRA full Prescribing Information and the Medication Guide, including Serious Side Effects, for more important safety information.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Hemophilia affects around 20,000 people in the United States, with hemophilia A being the most common form and approximately 50-60 percent of people living with a severe form of the disorder.

People with hemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with hemophilia A can bleed frequently, especially into their joints or muscles. These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility and long-term joint damage.

A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible, to obtain a level of factor VIII sufficient to control bleeding.

About Genentech in hemophilia

In 1984, Genentech scientists were the first to clone recombinant factor VIII in response to the contaminated hemophilia blood supply crisis of the early 1980s. For more than 20 years, Genentech has been developing medicines to bring innovative treatment options to people with diseases of the blood within oncology, and in hemophilia A. Genentech is committed to improving treatment and care in the hemophilia community by delivering meaningful science and clinical expertise. For more information visit http://www.gene.com/hemophilia.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.