Fremanezumab for refractory migraine in patients with hereditary transthyretin amyloidosis: A case series

Abstract

Background

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are considered a safe and well-tolerated option for migraine prophylaxis. However, caution is advised in patients with vascular comorbidities. In hereditary transthyretin amyloidosis (ATTRv amyloidosis), amyloid deposition in leptomeningeal vessels has been reported, potentially leading to cerebral amyloid angiopathy. The efficacy and safety of anti-CGRP antibodies in patients with this condition have not been described.

Methods

We present three patients with ATTRv amyloidosis and refractory migraine who were treated with 225 mg of fremanezumab monthly.

Results

All patients reported a reduction of more than 30% in the number of monthly headache and migraine days, as well a relief from maximum pain intensity and an improvement in quality-of-life impact scales. Mild constipation was reported by one patient, while the other two experienced no adverse effects.

Conclusion

In our experience, treatment with fremanezumab was both effective and safe in patients with ATTRv amyloidosis. To the best of our knowledge, this is the first reported use of anti-CGRP monoclonal antibodies in ATTRv amyloidosis patients with chronic migraine.

Introduction

The emergence of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) marked an important advance in migraine prevention. However, their use is often limited in the presence of certain comorbidities. Vascular conditions are of particular concern, as CGRP and its receptor are abundantly present in the vasculature and maintain cardiovascular homeostasis. Consequently blocking this system can therefore potentially worsen vascular events. ¹

Portugal has a high prevalence of hereditary transthyretin amyloidosis (ATTRv amyloidosis), due to val30met mutation. ² In our clinical experience, there is a high frequency of migraine in this population (unpublished data). Although specific data are lacking, it is common for patients to fail to respond to oral prophylactic treatments either due to lack of efficacy or side effects. Given this, the use of anti-CGRP drugs may offer a potential alternative option.

Theoretically, the use of monoclonal anti-CGRP antibodies in patients with ATTRv amyloidosis should be approached with caution, as cerebral amyloid angiopathy has been described in this disease. ³ In the early stages (within 3 years of the onset of peripheral neuropathy), TTR (transthyretin) amyloid deposits are already found in the meningeal vessels. As the condition progresses, these deposits become more widespread, eventually extending to the meningocortical arteries and the subpial region of the brain. ⁴ However, the prevalence and clinical significance of this remain unclear.

We present three cases of refractory migraine in patients with ATTRv amyloidosis treated with fremanezumab, highlighting its safety profile in this particular condition.

Results

Case 1

A 47-year-old woman was diagnosed with ATTRv amyloidosis (val30met mutation) at the age of 26, the same time as the onset of symptoms (distal hypoesthesia in lower limbs). Her mother also had the disease. She underwent liver transplant at the age of 31. At this time, headaches with migraine features started, and she met the criteria for migraine with aura. The brain magnetic resonance imaging (MRI) was normal. Over time, she developed a chronic migraine and tried multiple prophylactic drugs (topiramate, zonisamide, flunarizine, valproate, amitriptyline, venlafaxine, mirtazapine and sertraline), without clear improvement. Botulinum toxin (13 treatments, 195U PREEMPT protocol) improved mainly pain intensity, but she remained severely affected: 20 days of headache/month with overuse medication, with high impact in her quality of life. For this reason, monthly therapy with fremanezumab 225 mg was tried during 6 months and she improved to 10 days of headache/month (Table 1). In an attempt to improve efficacy, botulinum toxin was added, and after another 6 months of combined therapy, further improvement was noted, with no adverse side effects.

Table 1.

Characterisation of patients and clinical results.

Patient		1	2	3
Sex		F	F	M
Current age		47	51	51
Age at diagnosis of ATTRv amyloidosis		26	23	31
Mutation		val30met	val30met	val30met
Age at liver transplantation		31	31	35
Age of onset of migraine		31	16	35
Number of preventive drugs attempted		8	3	4
Months of treatment with botulinum toxin		36	58	9
Months of treatment with fremanezumab		6	12	12
Days of headache/month	Before	20	18	30
	After	10	3	15
Days of migraine/month	Before	20	16	17
	After	10	3	10
Days of analgesics/month	Before	5	0	30
	After	0	0	10
Days of triptans/month	Before	20	16	0
	After	10	3	0
Pain intensity (max 10)	Before	8	10	8
	After	5	9	7
MIDAS	Before	69	72	23
	After	9	15	10
HIT-6	Before	76	ND	64
	After	56	54	61
Adverse effect		No	No	Mild constipation

F: female; M: male; ND: no data; MIDAS: migraine disability assessment test (the score ranges from 0 to 270); HIT-6: headache impact test (the score ranges from 36 to 78).

Case 2

A 51-year-old woman was diagnosed with ATTRv amyloidosis (val30met mutation) at the age of 23 (her mother also had the disease), with the onset of symptoms at the age of 27 (distal hypoesthesia in the lower limbs). She underwent a liver transplant at the age of 31 and was re-transplanted at the age of 44. She had experienced headaches with migraine features since adolescence, which worsened in intensity and frequency after the first transplant. The brain computed tomography (CT) did not show any significant changes (MRI was not performed due to pacemaker). She had tried multiple prophylactic drugs (topiramate, zonisamide and mirtazapine) and botulinum toxin (58 months) but continued to meet the criteria for chronic migraine: 18 days of headaches/month with medication overuse and a significant impairment in her quality of life. After 12 months of monthly therapy with fremanezumab 225 mg, she improved to 3 days of headache/month and no adverse effects were reported (Table 1).

Case 3

A 51-year-old man was diagnosed with ATTRv amyloidosis (val30met mutation) at the age of 31, at the same time as the onset of symptoms (distal hypoesthesia in lower limbs). His mother also had the disease. He underwent a liver transplant at the age of 35. At that time, headaches began, and he met the criteria for migraine with aura. The brain CT did not show any significant changes (MRI was not performed due to pacemaker). He tried multiple prophylactic drugs (topiramate, zonisamide, verapamil and flunarizine), and botulinum toxin (9 months) but continued to experience daily headaches with medication overuse, significantly impacting his quality of life. After 12 months of monthly therapy with fremanezumab 225 mg, he improved in the number of monthly migraine days, which decreased to 10, and a clear reduction in analgesic use was noted. He reported mild constipation as an adverse effect (Table 1).

Discussion

We reported three patients with ATTRv amyloidosis and refractory migraine treated with fremanezumab, with clinical improvement and, most importantly, no major side effects. To the best of our knowledge, this is the first report of treatment with anti-CGRP mAbs in these patients. However, several questions were raised.

First, patients with ATTRv amyloidosis have been extensively studied concerning the risk of both haemorrhagic and ischaemic brain disease. ⁵ For this reason, we use anti-CGRP antibodies with caution, given their potential to interfere with the mechanisms and signalling pathways of cerebral vascular homeostasis. ⁶ Reports on their use in cerebral vasculopathies have seldom been documented. In 2019, a case was published describing a middle-aged CADASIL patient treated with erenumab. The patient showed a favourable response with no adverse effects, suggesting that this therapy may be safe even in patients with vascular comorbidities. ⁷ Nevertheless, guidelines continued to recommend caution in the presence of vascular disease or risk factors. ⁸

For this reason, we considered that the most prudent approach would be to complement clinical monitoring with baseline and periodic brain MRI. However, in the ATTRv population, the presence of a pacemaker is common in longstanding disease, ³ posing practical challenges to this recommendation.

Another major concern was the duration of treatment. Since there are still few studies on the long-term use of anti-CGRP antibodies,^{9, 10} we adhered to the recommended treatment duration of 12 to 18 months. ⁸

Constipation was also a concern, as it has been reported with anti-CGRP treatments,^11,12 and dysautonomic complains are common in patients with ATTRv amyloidosis. ¹³ Indeed, in patients already predisposed to dysautonomic symptoms, compliance with continued treatment with anti-CGRP mAbs could be challenging. For this reason, fremanezumab was chosen for our cohort because, despite having variable odds ratio for constipation in a recent review (paradoxically lower with a dose of 675 mg than with a dose of 225 mg), it was considered the anti-CGRP monoclonal antibody with the lowest likelihood of treatment interruption due to adverse effects overall. ¹⁴

Finally, although the overall safety and tolerability of anti-CGRP antibodies is well established, autoimmune hepatitis has been reported on the 14th day of treatment with erenumab, suggesting a potential causality besides the temporal relationship of events. ¹⁵ This is particularly concerning for patients who have undergone liver transplant.

Because of this, we conducted close and regular clinical and laboratory monitoring, including hepatic parameters, which remain stable.

Regarding efficacy, all patients reduced their number of headaches and migraine days per month by more than 30%, along with a decrease in the use of abortive drugs (analgesics and triptans). They also experienced some relief from maximum pain intensity and the quality-of-life impact scales reflected their satisfaction and improvement (Table 1).

Limitations

This is a small case series with only 1 year of follow up, therefore, the generalisability of our findings is limited. These patients are the only ones with ATTR amyloidosis and migraine who have initiated anti-CGRP treatment in our Neurology Department. The positive results observed suggest that anti-CGRP antibodies may be a viable alternative for patients with ATTRv amyloidosis and refractory migraine. However, a longer follow-up period is needed to thoroughly assess the safety of this treatment in this population.

Conclusion

In our experience, treatment with fremanezumab in patients with ATTRv amyloidosis was both effective and safe. To the best of our knowledge, this is the first report on the use of anti-CGRP monoclonal antibodies in ATTRv amyloidosis patients with chronic migraine.

Clinical implications

Safety: Fremanezumab was well-tolerated, with no significant safety concerns observed in our cases.

Potential therapeutic benefit: Given its effectiveness and safety profile, fremanezumab, or other anti-CGRP antibodies, may represent a promising treatment option for patients with refractory migraine and ATTRv amyloidosis.

Need for further research: While the results are promising, a longer follow-up period is needed to confirm these findings and evaluate long-term outcomes.