Deepti Saxena Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Correspondence to: Dr Deepti SaxenaEmail:saxenadrdeepti@gmail.com
1 Burosumab in X-linked hypophosphatemia (Carpenter et al., 2018)
X-linked hypophosphatemia, the most common heritable form of rickets, is caused due to loss-of-function mutations in the
PHEX gene. It is characterized by increased secretion of fibroblast growth factor 23 (FGF-23) which leads to renal
phosphate wasting, hypophosphatemia, rickets and osteomalacia, stunted growth, skeletal deformity, pain and limitation
of daily activities. Conventional therapy with oral phosphate salts and vitamin D analogues is associated with poor
compliance, incomplete healing of rickets, residual skeletal deformity, persistent short stature, gastrointestinal side
effects and risks of hypercalciuria, nephrocalcinosis, and hyperparathyroidism. Burosumab is a recombinant
human IgG1 monoclonal antibody that targets FGF-23. The authors have studied the effect of Burosumab
in children aged 5-12 years. A total of 52 cases with active rickets and confirmed diagnosis of X-linked
hypophosphatemia were taken. The authors concluded that 2 weekly regimen provided a sustained increase in the serum
phosphorus level. There was substantial healing of rickets in all children with severe rickets with improvements in
multiple related efficacy endpoints. However, effect on adult height is unknown which will take years to
evaluate. Also, long term treatment is required for proper assessment of joint related complications and risk of
nephrocalcinosis.
2 Intraventricular Cerliponase Alfa for CLN2 Disease (Schulz et al., 2018)
Neuronal ceroid lipofuscinosis type 2 is a rare neurodegenerative disorder characterized by seizures and rapid
decline in vision, motor, language, and cognitive functions. It is an autosomal recessive condition caused due
to deficiency of the lysosomal enzyme Tripeptidyl peptidase 1 (TPP1). Cerliponase alfa is a recombinant
form of human TPP1 and can be used as an enzyme-replacement therapy in patients with CLN2. In this
study, the authors have evaluated the role of Cerliponase alfa in children with CLN2. A total of 24 children
between the ages of 3 to 16 years were enrolled and they received intraventricular infusions of 300 mg every
2 weekly for a total duration of 96 weeks. The authors have concluded that intraventricular infusion of
cerliponase alfa is associated with less decline in motor and language function as compared to historical
cohorts.
3 Prophylaxis for hereditary angioedema (Syed et al., 2018)
Hereditary angioedema is an autosomal dominant condition characterized by recurrent attacks of angioedema.
It is caused due to mutation in the SERPING1 gene encoding C1 inhibitor. There may be reduction in
levels of C1INH (C1 esterase Inhibitor) or there may be reduced functional activity leading to uncontrolled
activity of plasma kallikrein causing excessive bradykinin production and angioedema. Lanadelumab is a
human monoclonal antibody that inhibits plasma kallikrein. This drug has been approved for prophylactic
use by US FDA in patients aged more than 12 years. The drug is given subcutaneously and can be self –
administered.
4 Vestronidase alfa for mucopolysaccharidosis VII (Harmatz et al., 2018)
Mucopolysaccharidosis type VII is a rare genetic disorder caused by deficiency of the lysosomal enzyme
β-glucuronidase. The authors have used blind start trial design due to the small number of patients. A total of 12
patients were divided into four groups. After 24 weeks of treatment with Vestronidase, there was a significant
reduction in urinary glycosaminoglycan excretion. Ten patients had improvement in the overall clinical outcome
scores.
5 Emicizumab prophylaxis in Hemophilia A patients with or without FVIII inhibitors (Le Quellec et al., 2018)
Emicizumab is a recombinant monoclonal antibody that acts as a bridge between activated Factor IX and Factor X and
thereby mimics the function of Factor VIII. In the phase 3 HAVEN1 trial conducted on 109 Hemophilia A patients, once
weekly subcutaneous dosage regimen was found to maintain lowest factor levels to at least 10-15 IU/dl. It
was also found that Emicizumab prophylaxis significantly reduced the bleeding episodes as compared to
conventional episodic treatment with bypassing agents in case of patients with inhibitors against Factor
VIII. There is increased risk of thrombotic events especially if the drug is used along with bypassing agents
(BPAs) such as activated Prothrombin Complex Concentrates (aPCCs) and recombinant factor VIIa (rVIIa)
during the episodes of breakthrough bleeding. There are concerns over use of this drug versus use of immune
tolerance induction (ITI) therapy in children with inhibitors, as treatment with Factor VIII is more effective in
comparison to BPAs in case of breakthrough bleeds. Also, as there is increased risk of thrombosis associated with
BPAs, it has been proposed to start prophylaxis with Emicizumab along with ITI therapy in children with
inhibitors.
References
1. Carpenter TO, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med
2018; 378:1987-1998.
2. Harmatz P, et al. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis
VII, an ultra-rare genetic disease. Mol Genet Metab 2018; 123: 488-494.
3. Le Quellec S, Negrier C. Emicizumab should be prescribed independent of immune tolerance induction.
Blood Adv 2018; 2: 2783-2786.
4. Schulz A, et al. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med 2018; 378:
1898-1907.
5. Syed YY. Lanadelumab: First Global Approval. Drugs 2018; 78:1633-1637.