Efficacy and safety of givosiran in Japanese patients with acute hepatic porphyria: Clinical findings from an expanded access study

doi:10.21203/rs.3.rs-5201348/v1

Acute hepatic porphyria (AHP), a rare genetic disorder, causes life-threatening porphyria attacks and chronic pain and impairs daily functioning and quality of life. Recently, a new siRNA therapy, givosiran, became available for AHP. This open-label, multicenter, single-arm study expanded access to givosiran and further explored its safety and efficacy in 10 Japanese patients with AHP. Participants received monthly subcutaneous injections of givosiran (2.5 mg/kg). Three patients were continued from the phase III ENVISION study of givosiran, and seven were newly recruited. Assessments comprised clinical AHP features, urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, use of hemin to treat attacks, and the Givosiran Patient Experience Questionnaire (GPEQ). Urinary ALA and PBG levels remained at or below upper limits of normal levels throughout the study. The GPEQ showed symptomatic improvement in eight participants. Of the eight adverse events, five were deemed by the investigator to be related to givosiran. One patient experienced two attacks, which required urgent healthcare visits but no hemin use. Generally, the safety profile was consistent with that previously observed. All adverse events were nonserious, and no deaths occurred. The study indicates that monthly givosiran administration is safe and clinically useful in Japanese patients with AHP.

Health sciences/Diseases

Health sciences/Gastroenterology

givosiran

acute hepatic porphyria

quality of life

Acute hepatic porphyria (AHP) is a group of rare, chronic, multisystem disorders characterized by acute porphyria attacks, progressive elements, and long-term complications requiring proactive management and treatment. AHP comprises the following four types: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and aminolevulinic acid dehydratase-deficient porphyria (ADP) [1]. The underlying mechanism commonly leads to a reduction in heme produced and an accumulation of heme precursors. Acute porphyrias are primally manifest as neurological attacks due to increasing production of neurotoxic precursors. To date, fewer than 100 cases of AHP have been identified in Japan [2].

In most cases, AHP is characterized by potentially life-threatening acute attacks, but some patients have chronic manifestations and progressive disease with respiratory failure and paralysis in rare cases, which can impair daily functioning and quality of life (QOL) [1]. Patients also report that acute attacks reduce QOL and affect personal relationships because the attacks cause feelings of isolation and patients have difficulty adjusting to disease limitations [3]. AHP impacts many aspects of daily living, e.g., it alters sleep patterns, reduces the ability to work, causes walking abnormalities, affects finances and socialization, and increases medical costs [4, 5]. Even in patients with a low rate of acute attacks or prolonged periods without attacks, AHP remains a chronically symptomatic disease that adversely affects health and QOL [3, 6, 7].

Givosiran (brand name: GIVLAARI®, subcutaneous injection; Alnylam Pharmaceuticals, MA, USA) is a chemically synthesized double-stranded small interfering RNA that targets the messenger RNA of the 5’-aminolevulinic acid synthase 1 gene in the liver and is a therapeutic agent for treating AHP [8]. The phase III ENVISION trial in 94 patients with AHP revealed that compared with placebo, givosiran significantly reduced the annualized number of composite porphyria attacks (i.e., attacks requiring hospitalization, emergency visits, or intravenous hemin at home) and QOL improvement via exploratory endpoints [9]. These findings indicated that givosiran may be an essential treatment option for improving QOL in patients with AHP.

On the basis of the ENVISION study results, givosiran was approved for the treatment of AHP in adults by the US Food and Drug Administration (FDA) on November 20, 2019, and by the European Medicines Agency (EMA) on March 2020; the EMA also approved the use of givosiran in adolescents older than 12 years of age. After the FDA and EMA approvals, in June 2020 givosiran was designated as an orphan drug in Japan, and in June 2021, it was approved by the Japanese Ministry of Health, Labor and Welfare for treatment of AHP.

Before the approval of this drug in Japan, this expanded access study was designed to provide access to investigational givosiran for patients with AHP who have limited or no available treatment options and for whom the treating physician believes the benefits outweigh the risks. The clinical findings in patients enrolled this study were described in an exploratory manner.

Study design

This was an open-label, multicenter, single-arm, expanded-access study that was performed while the regulatory authorities were considering approval of givosiran in Japan. The study started on February 2, 2021. The plan was that if givosiran was approved for treatment in Japan during the course of the study, the study would be terminated within 180 days of approval; in that case, eligible patients would be given the option to transfer to a commercial givosiran regimen. In fact, givosiran was approved in Japan on June 23, 2021, so the last patient finished the study on December 8, 2021.

The study was registered in the Japan Registry of Clinical Trials (JRCT) on December 24, 2020 (registration number: JRCT2071200074; https://jrct.niph.go.jp/en-latest-detail/jRCT2071200074), and the study protocol was approved by the Ethics Committee of Iizuka Hospital, Fukuoka, Japan (approval no. 2020-6 ,7th Dec. 2020 ). The actual date of first enrollment was February 2, 2021.

Study population

The study population included patients older than 12 years with a diagnosis of one of the four types of AHP, i.e., AIP, HCP, VP, or ADP. Details of the eligibility requirements are provided in the supplementary information (see Supplementary Methods, Inclusion and Exclusion Criteria). Patients were either newly recruited and had not previously received givosiran treatment or were enrolled in this study after participating in the multicenter, global Phase III clinical study of givosiran (the ENVISION study, which was performed from November 16, 2017, through January 31, 2019).

All patients provided written informed consent, and the study adhered to the Declaration of Helsinki guidelines.

Study drug and endpoints

Enrolled patients received a monthly subcutaneous injection of 2.5 mg/kg of givosiran, which was supplied by Alnylam Pharmaceuticals (Cambridge, MA, USA). The efficacy of givosiran was evaluated with the following exploratory endpoints, which were measured and checked at baseline and 6 months of this study: urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, number of porphyria attacks (see Supplementary Methods, Definition of Porphyria Attacks and Porphyria Attack Form), patient-reported hemin administration, patient outcomes reported with the Givosiran Patient Experience Questionnaire (GPEQ; see Supplementary Methods, Givosiran Patient Experience Questionnaire), and incidence of treatment-emergent adverse events (TEAEs).

Outcome measures and statistical analysis

Statistical analysis was performed primarily with descriptive statistics, such as mean, standard deviation, median, minimum, and maximum values for continuous variables and frequencies and percentages for categorical and ordinal variables. The incidence of TEAEs was tabulated, and TEAEs for which a causal relationship could not be ruled out were summarized as treatment-related adverse events (TRAE). Statistical analyses were performed with SAS statistical software version 9.4 (Cary, NC, USA).

Patient disposition and baseline characteristics

Eight sites enrolled a total of 10 patients, including three from the ENVISION study and seven givosiran-naive patients. In all 10 patients, givosiran was administered for seven to 11 months. However, one patient discontinued the study after six months (after receiving six doses of givosiran) because of a TEAE (see Safety section below). All 10 enrolled patients were included in the safety and exploratory efficacy analyses.

The patient baseline characteristics are shown in Table 1. The seven newly included patients had a higher mean and median age, and all of them were women. Three of the seven newly included patients and all three of the patients from the ENVISION study had a history of hemin use. The three patients from the ENVISION study had AIP or VP, whereas the seven newly included patients had AIP or HCP; none of the patients had ADP.

Exploratory efficacy analysis

Urine ALA and PBG levels

The changes in urinary ALA and PBG levels are shown in Fig. 1. In the three patients from the ENVISION study, urinary ALA and PBG levels were low at baseline (0.919 ± 0.297 mmol/mol and 2.168 ± 1.611 mmol/mol, respectively) and remained low throughout the study period (0.725 ± 0.731 mmol/mol and 2.336 ± 3.481 mmol/mol, respectively, at month 6 [n=3], and 1.082 ± 0.853 mmol/mol and 1.409 ± 1.321 mmol/mol, respectively, at the end of the study [n=2]). In the seven newly included patients, baseline urinary ALA and PBG levels were 6- and 102-fold higher (203.287 ± 514.325 mmol/mol and 258.125 ± 655.154 mmol/mol, respectively) than the upper limits of normal in healthy individuals (ALA, 1.47 mmol/mol; PBG, 0.137 mmol/mol). Both ALA and PBG levels decreased and remained low after treatment with givosiran (1.760 ± 2.795 mmol/mol and 2.116 ± 3.893 mmol/mol, respectively, at month 6 [n=7] and 0.837 ± 0.222 mmol/mol and 0.830 ± 0.178 mmol/mol, respectively, at the end of the study [n=3]).

Porphyria attacks and hemin administration during the study

Attacks were reported by two of the 10 patients, both of whom had participated in the ENVISION study (Table 2). In the present study, one of these two patients reported one attack, and the other seven attacks. The patient with one attack did not require an urgent healthcare visit, but the patient with seven attacks required two urgent healthcare visits. None of the attacks in either patient required hospitalization or hemin treatment. All other attacks were treated by home health care, i.e., carbohydrates or analgesics.

GPEQ patient-reported outcomes

Table 3 shows patients’ overall evaluation of givosiran according to the GPEQ results at the end of the study compared with the GPEQ results at baseline. Eight of the 10 patients (80%) reported some improvement, including all three patients from the ENVISION study. No change or a minimal worsening was reported only by givosiran-naive patients. For the improvement in QOL from the perspective of symptoms and physical problems, the percentage of responses in the categories “A lot better” or “Better” was slightly higher among the newly recruited patients than among those from the ENVISION study (Table 4), but for the improvement in QOL from the perspective of emotional and social aspects, the percentage of responses in those two categories was substantially higher among the patients from the ENVISION study than among the newly recruited patients (Table 5). In addition, only one patient, who was from the ENVISION study, responded with “A lot worse” to any of the items.

Safety

Regarding AEs, at least one TEAE occurred in eight of the 10 patients. Five TEAEs were deemed by the study investigators to be associated with the study drug. All TEAEs were nonserious and mild or moderate in severity. However, one patient discontinued treatment because of mild alopecia, which was deemed by the investigator to be associated with the study drug. No deaths occurred. Table 6 summarizes the TEAEs suspected by the investigators to be causally related to the study drug.

The study included a total of 10 patients (three from the ENVISION study and seven who were naive to givosiran treatment). After givosiran administration, urinary ALA and PBG levels were almost normal in all 10 patients. Only two patients experienced porphyria attacks during the study; one had seven attacks, and the other had one attack. However, no attacks required hospitalization or hemin administration. Regarding QOL, eight of 10 patients reported improvement compared with baseline. Nonserious AEs were observed in eight patients; one of these patients, who developed mild alopecia related to givosiran, withdrew from the study.

Patient satisfaction ratings tended to be higher among the continuing patients from the ENVISION study than among the newly recruited ones. Even the patient who had seven attacks (and who—according to the patient’s attending physician [one of the investigators]—had been hospitalized due to an attack before receiving givosiran) experienced overall improvement after givosiran administration in that, apart from two urgent healthcare visits, she could manage her attacks at home. Moreover, the numbness in her limbs, which had caused difficulty in walking, improved to the extent that she could walk to the hospital. These findings may indicate that long-term treatment with givosiran would be beneficial in patients with AHP.

On the other hand, the new patient with the lowest overall GPEQ score indicated that the regular hospital visits for treatment administration added burden to their disease manifestation, highlighting the challenges of managing AHP. Even in patients with a low rate of acute attacks or prolonged periods without attacks, AHP remains a chronically symptomatic disease that adversely affects health and QOL [4, 7, 8]. The two patients whose GPEQ scores did not clearly improve after 6 months with givosiran treatment had decreased urinary ALA and PBG levels, suggesting that a longer treatment period may be required for their GPEQ to improve. The experience of these patients makes clear the difficulties in treating AHP.

As regards the safety analyses, the patient who discontinued treatment because of mild alopecia was a newly included patient. To our knowledge, this is the first time that alopecia has been reported in patients treated with givosiran. The patient reported that the treatment felt effective but that she withdrew from the study because of the importance of her appearance. Despite the resolution of the alopecia symptoms after drug discontinuation, she was hesitant to resume treatment because of concerns regarding a recurrence of the alopecia.

It is noteworthy that the patients from the ENVISION study received longer treatment (range, 41–45 months) and appeared to report greater benefit than the newly recruited patients who received 5 to 9 months of treatment. These data are consistent with the results from the ENVISION longer term study [9]. Interestingly, a recently presented post hoc study showed that although all patients had fewer attacks and other treatment-related outcomes at 6 months, the patients who were not attack free at 6 months reported further attack reductions and QOL improvements with longer term givosiran treatment, with the majority of patients from both groups showing greater benefit after 30 to 36 months of treatment. [13].

In the ENVISION study, an attack was defined as an event that required hospitalization, urgent care, or home infusion of hemin [8]. When this definition was applied to the present study, only one of the two patients who reported porphyria attacks during the study would be considered to have an attack according to the ENVISION study definition, i.e., two attacks that required urgent care visits during a treatment period of approximately 9 months. This patient had 6 attacks/year during the ENVISION study. Another patient who had 12 attacks during the ENVISION study had one attack during the present study, but the attack did not meet the ENVISION study definition of an attack. None of the seven newly enrolled patients had any attacks. Despite the differences in the definition of an attack between the ENVISION study and this study, both studies demonstrate the benefit of givosiran treatment.

The study has several limitations because it was performed to provide expanded access, so rigorous evaluation was difficult. No interviews were performed to assess the occurrence and severity of AHP symptoms and attacks before givosiran administration. In addition, no unified assessment was performed of other factors that affect symptoms and QOL during givosiran treatment; however, the GPEQ results suggest that the health status of many continuing and new patients improved after they received the drug.

Until the approval of givosiran, treatment options for AHP were limited and focused on supportive care. In addition to the ENVISION study, this expanded access study demonstrates the benefits and acceptable safety profile of monthly givosiran administration in patients with AHP.

Data availability

The data supporting the findings of this study are either included in the article or available from the corresponding author upon reasonable request.

Acknowledgments

We wish to thank all the study participants and their families. We also thank the following physicians and the staff at their hospitals for their cooperation in performing this study: Dr. Yutaka Horie, Department of Digestive Organs Shimaneken Saiseikai Gotsu General Hospital, Shimane, Japan; Dr. Makoto Daimon, Graduate School of Medicine Medical Science Course Endocrinology and Metabolism, Hirosaki University, Aomori, Japan; Dr. Shinji Susa, Internal Medicine III, Yamagata University Hospital, Yamagata, Japan; Drs. Takashi Nakahara and Atsushi Oono, Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan; Dr. Takanori Kudo, Department of Endocrinology and Diabetes, Hachinohe City Hospital, Aomori, Japan; and Drs. Kei-ichirou Takase and Keita Sonoda, Department of Neurology, Iizuka Hospital, Fukuoka, Japan. We thank Mary-Jean Fanelli for leading this study; CMIC CO., Ltd., Tokyo, Japan for their assistance in conducting the clinical trial; and Yuka Yasuoka of Alnylam Japan K.K. for her assistance in creating this manuscript.

Funding

This study was funded by Alnylam Japan K.K., Tokyo, Japan, and was also supported by funding from Alnylam Pharmaceuticals, Cambridge, MA, USA.

Author information

Authors and Affiliations

Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Aichi, Japan

Nobuaki Ozaki

JA Shizuoka Kohseiren Enshu Hospital, Shizuoka, Japan

Yoshie Goto

Alnylam Japan K.K., Tokyo, Japan

Norihisa Fujii, Takuro Oyama

Alnylam Pharmaceuticals, Cambridge, MA, USA

Karen Frascello, Ana Camejo

Tokyo Saiseikai Central Hospital, Tokyo, Japan

Tomohide Adachi

Contributions

All authors contributed substantially to this work. NF formulated and designed this study. NO, YG, TO, KF, and TA gathered data. All authors contributed to data analysis and interpretation, read and revised the manuscript, and approved the submission of the final version.

Corresponding author

Correspondence to Takuro Oyama ([email protected])

Ethics declarations

Competing interests

NF and TO are employees of Alnylam Japan K.K., KF is an employee of Alnylam Pharmaceuticals Inc., and AC is a former employee of Alnylam Pharmaceuticals Inc. The authors declare no other conflicts of interest.

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Iizuka Hospital, Fukuoka, Japan (approval no. 2020-6, 7^th Dec. 2020). Written informed consent was obtained from all patients before inclusion in the study.

Additional information

Prior publication

A preprint of this article was uploaded to Research Square (https://assets-eu.researchsquare.com/files/rs-2694737/v1/5afae31b-d9d8-46e7-9a86-8c17e4d0e308.pdf?c=1692792780)

Bissell, D. M. & Wang, B. Acute hepatic porphyria. J. Clin. Transl Hepatol. 3, 17–26 (2015).
Kondo, M., Yano, Y. & Urata, G. Japanese hereditary porphyria: Aggregation for 91 years from 1920 to 2010. ALA-Porphyrin Sci. 2, 73–82 (2012).
Dickey, A. et al. Quantifying the impact of symptomatic acute hepatic porphyria on well-being via patient-reported outcomes: Results from the Porphyria Worldwide Patient Experience Research (POWER) study. JIMD Rep. 64, 104–113 (2022).
Simon, A. et al. Patient perspective on acute intermittent porphyria with frequent attacks: A disease with intermittent and chronic manifestations. Patient. 11, 527–537 (2018).
Francesca, G., Nicolli, A., Colaioc, A., Di Pierro, E. & Graziadei, G. Psychological aspect and quality of life in porphyrias: A review. Diagnostics 12, 1193 (2022).
Buendia-Martinez, J. et al. Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients. Orphanet J. Rare Dis. 16, 106 (2021).
Wheeden, K. et al. Patient perspective on acute hepatic porphyria with sporadic attacks: A chronic disease with substantial health-related quality of life impacts. Adv. Ther. 39, 4330–4345 (2022).
Scott, L. J. & Givosiran First approval. Drugs. 80, 335–339 (2020).
Kuter, D. J. et al. Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial. J. Hepatol. 79, 1150–1158 (2023).
Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl. J. Med. 382, 2289–2301 (2020).
Wang, B. et al. Disease burden in patients with acute hepatic porphyria: Experience from the phase 3 ENVISION study. Orphanet J. Rare Dis. 17, 327 (2022).
Ventura, P. et al. Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study. Liver Int. 42, 161–172 (2022).
Ventura, P. et al. Long-term clinical outcomes of patients with acute hepatic porphyria who were not attack-free after 6 months of givosiran treatment in a subgroup analysis of the phase 3 ENVISION study. J. Hepatol. 80 (S1), S715 (2024).

Table 1. Baseline demographic and clinical characteristics (efficacy analysis population)

	From ENVISION study (n=3)	Not from ENVISION study (n=7)	All patients (N=10)
Age, y
Mean (s.d.)	36.0 (14.1)	43.9 (12.5)	41.5 (12.8)
Median	34.0	45.0	43.5
Min, Max	23, 51	22, 61	22, 61
Sex, n (%)
Male	1 (33.3)	0	1 (10.0)
Female	2 (66.7)	7 (100)	9 (90.0)
Weight, kg
Mean (s.d.)	58.8 (10.9)	57.8 (11.3)	58.1 (10.5)
Median	60.1	60.3	60.2
Min, Max	47.3, 69.0	41.6, 74.2	41.6, 74.2
Race, n (%)
Asian	2 (66.7)	7 (100)	9 (90.0)
Mixed	1 (33.3)	0	1 (10.0)
History of hemin use, n (%)
No	0	3 (42.9)	3 (30.0)
Yes	3 (100)	4 (57.1)	7 (70.0)
Type of AHP, n (%)
AIP	2 (66.7)	5 (71.4)	7 (70.0)
VP	1 (33.3)	0	1 (10.0)
HCP	0	2 (28.6)	2 (20.0)
ADP	0	0	0

Abbreviations: ADP, aminolevulinic acid dehydratase-deficient porphyria; AHP, acute hepatic porphyria; AIP, acute intermittent porphyria; HCP, hereditary coproporphyria; Max, maximum; Min,: minimum; n, number; s.d., standard deviation; VP, variegate porphyria

Table 2. Patient details

ID	ENVISION Participation	Type	Age	Sex	History of hemin use	Remarks	Overall status
1	Yes	AIP	23	Female	Yes	One attack during the study period	Very much improved
2	Yes	AIP	51	Male	Yes		Much improved
3	Yes	VP	34	Female	Yes	Seven attacks during the study period (2 urgent care visits)	Minimally improved
4	No	AIP	45	Female	Yes	Discontinued because of onset of alopecia (mild)	Very much improved
5	No	HCP	22	Female	No		Very much improved
6	No	HCP	61	Female	Yes		Much improved
7	No	AIP	42	Female	Yes		Much improved
8	No	AIP	53	Female	No		Much improved
9	No	AIP	36	Female	Yes	Missed several doses because of liver dysfunction	No change
10	No	AIP	48	Female	No	Felt stressed by scheduled clinical visits	Minimally worse

Abbreviations: AIP, acute intermittent porphyria; HCP, hereditary coproporphyria; VP, variegate porphyria

Table 3. Givosiran Patient Experience Questionnaire findings of changes in overall status as a result of givosiran treatment (Efficacy Analysis Population)

	From ENVISION study (n=3)	Not from ENVISION study (n=7)	All patients (N=10)
	n (%)	n (%)	n (%)
Since the start of the study, my overall status is:
Very much improved	1 (33.3)	2 (28.6)	3 (30.0)
Much improved	1 (33.3)	3 (42.9)	4 (40.0)
Minimally improved	1 (33.3)	0	1 (10.0)
No change	0	1 (14.3)	1 (10.0)
Minimally worse	0	1 (14.3)	1 (10.0)
Much worse	0	0	0
Very much worse	0	0	0

Table 4. Improvement in quality of life: symptoms and physical problems

Table 4a: Whole group (N=10)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Pain	3	2	4	0	0	1
Fatigue	1	2	5	1	0	1
Constipation	0	0	6	1	0	3
Diarrhea	0	0	6	0	0	4
Appetite loss	1	1	5	0	0	3
Concentration problems	0	1	5	0	0	4
Numbness	0	1	3	1	0	5
Tingling	0	2	4	0	0	4
Muscle weakness	0	2	5	0	0	3
Insomnia (problems falling and/or staying asleep)	0	3	4	1	1	1
Total responses for each outcome*	5 (5.0%)	14 (14.0%)	47 (47.0%)	4 (4.0%)	1 (1.0%)	29 (29.0%)

* The % value represents indicates the total rate of patient responses reported for each outcome as a percentage of the total of 100 possible responses (N=10 patients rated 10 outcomes).

Table 4b: Patients from the ENVISION study (n=3)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Pain	0	2	1	0	0	0
Fatigue	1	1	0	1	0	0
Constipation	0	0	2	0	0	1
Diarrhea	0	0	2	0	0	1
Appetite loss	0	1	2	0	0	0
Concentration problems	0	1	1	0	0	1
Numbness	0	0	2	1	0	0
Tingling	0	1	2	0	0	0
Muscle weakness	0	1	2	0	0	0
Insomnia (problems falling and/or staying asleep)	0	2	0	1	0	0
Total responses for each outcome*	1 (3.3%)	9 (3.0%)	14 (46.7%)	3 (10.0%)	0	3 (10.0%)

* The % value represents the total responses for each outcome as a percentage of the total of 30 possible responses (n=3 patients rated 10 outcomes).

Table 4c: Patients not from the EVISION study (n=7)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Pain	3	0	3	0	0	1
Fatigue	0	1	5	0	0	1
Constipation	0	0	4	1	0	2
Diarrhea	0	0	4	0	0	3
Appetite loss	1	0	3	0	0	3
Concentration problems	0	0	4	0	0	3
Numbness	0	1	1	0	0	5
Tingling	0	1	2	0	0	4
Muscle weakness	0	1	3	0	0	3
Insomnia (problems falling and/or staying asleep)	0	1	4	0	1	1
Total responses for each outcome*	4 (5.7%)	5 (7.1%)	33 (47.1%)	1 (1.4%)	1 (1.4%)	26 (37.1%)

*The % value represents the total responses for each outcome as a percentage of the total of 70 possible responses (n=7 patients rated 10 outcomes).

Table 5. Improvement in quality of life: emotional and social aspects

Table 5a: Whole group (N=10)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Depression	0	2	2	0	1	5
Anxiety	2	2	3	0	1	2
Traveling for work or pleasure	2	1	5	1	0	1
Planning ahead (schedules, appointments, etc.)	1	1	5	0	1	2
Ability to meet friends or family outside the house	2	1	4	1	0	2
Ability to do the things you enjoy doing	1	3	3	0	1	2
Ability to do things independently	1	3	3	0	1	2
Feeling like you are a burden to your family	2	2	4	0	1	1
Ability to work	1	3	4	0	1	1
Total responses for each outcome*	12 (13.3%)	18 (20.0%)	33 (36.7%)	2 (2.2%)	7 (7.8%)	18 (20.0%)

*The % value represents the total responses for each outcome as a percentage of the total of 90 possible responses (N=10 patients rated 9 outcomes).

Table 5b: Patients from ENVISION study (n=3)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Depression	0	2	0	0	0	1
Anxiety	1	1	0	0	0	1
Travelling for work or pleasure	2	0	1	0	0	0
Planning ahead (schedules, appointments, etc.)	1	1	1	0	0	0
Ability to meet friends or family outside the house	2	0	1	0	0	0
Ability to do the things you enjoy doing	1	1	1	0	0	0
Ability to do things independently	1	1	1	0	0	0
Feeling like you are a burden to your family	2	1	0	0	0	0
Ability to work	1	1	1	0	0	0
Total responses for each outcome*	11 (40.7%)	8 (29.6%)	6 (22.2%)	0	0	2 (7.4%)

*The % value represents the total responses for each outcome as a percentage of the total of 27 possible responses (n=3 patients rated 9 outcomes).

Table 5c: Patients not from EVISION study (n=7)

	A lot better	Better	No change	Worse	A lot worse	Does not apply
	n	n	n	n	n	n
Depression	0	0	2	0	1	4
Anxiety	1	1	3	0	1	1
Traveling for work or pleasure	0	1	4	1	0	1
Planning ahead (schedules, appointments, etc.)	0	0	4	0	1	2
Ability to meet friends or family outside the house	0	1	3	1	0	2
Ability to do the things you enjoy doing	0	2	2	0	1	2
Ability to do things independently	0	2	2	0	1	2
Feeling like you are a burden to your family	0	1	4	0	1	1
Ability to work	0	2	3	0	1	1
Total responses for each outcome*	1 (1.6%)	10 (15.9%)	27 (42.9%)	2 (3.2%)	７ (11.1%)	16 (25.4%)

*The % value represents the total responses for each outcome as a percentage of the total of 63 possible responses (n=7 patients rated 9 outcomes).

Table 6. Treatment-emergent adverse events associated with the study treatment according to the system organ class and preferred term (Safety Analysis Population)

SOC PT	Safety Analysis Population (N=10) n (%)
Number of patients reporting at least one TEAE associated with study treatment	5 (50)
General disorders and administration site conditions	1 (10)
Infusion site erythema	1 (10)
Edema	1 (10)
Investigations	2 (20)
Alanine aminotransferase increased	1 (10)
Aspartate aminotransferase increased	1 (10)
Blood alkaline phosphatase increased	1 (10)
Blood homocysteine increased	1 (10)
Gamma-glutamyl transferase increased	1 (10)
Liver function tests increased	1 (10)
Metabolism and nutrition disorders	1 (10)
Hyperhomocysteinemia	1 (10)
Renal and urinary disorders	1 (10)
Renal impairment	1 (10)
Skin and subcutaneous tissue disorders	2 (20)
Alopecia	2 (20)

Abbreviations: PT, preferred term; SOC, system organ class; TEAE, treatment-emergent adverse event

Treatment-emergent adverse events were defined as any adverse events that started or worsened after exposure to the study drug.

Competing interest reported. NF and TO are employees of Alnylam Japan K.K., KF is an employee of Alnylam Pharmaceuticals Inc., and AC is a former employee of Alnylam Pharmaceuticals Inc. The authors declare no other conflicts of interest.

Supplmethods0829editednomarkups.pdf

Efficacy and safety of givosiran in Japanese patients with acute hepatic porphyria: Clinical findings from an expanded access study

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Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

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