Patisiran

Mechanism of Action

Mechanism of Action

Patisiran, a novel treatment for polyneuropathy associated with hATTR, is a small, double-stranded interfering RNA molecule (ALN-18328) formulated in a lipid covering using micro nanotechnology.[15][16] This nanoparticle also contains two novel lipid excipients (PEG-C-DMG and DLin-MC3-DMA) to facilitate siRNA entry into the target cell cytoplasm.[17]

Patisiran is administered via intravenous infusion and transported to the liver by blood. The apolipoprotein opsonized in the lipid capsule of the nanoparticle is recognized by the apolipoprotein-E receptors of hepatocytes, and the drug internalizes by endocytosis. The disruption of the nanoparticles in hepatocytes releases the pharmacologically active moiety siRNA. Then, siRNA processing by the ribonuclease, also known as the Dicer enzyme, occurs. This processing involves cleaving the overhanging nucleotides on the edges of the siRNA. The processed siRNA binds to the RNA-induced silencing complex (RISC).

This RISC separates the strands of the siRNA sequence. One strand releases, and the other one remains bound to the RISC. Then, the bound strand of siRNA functions as a targeting sequence for the complementary mRNA sequence. The bound patisiran strand binds to the genetically conserved sequence located in the 3' untranslated region of the complementary mRNA encoding abnormal transthyretin (TTR) and the alignment of the RISC complex with it.[1] 

Subsequently, transthyretin mRNA is cleaved to render it nonfunctional. The degradation of mRNA coding wild-type and mutant transthyretin (TTR), a process of post-transcriptional gene silencing, results in reduced levels of TTR protein in the serum and ultimately deposition of TTR protein, also called amyloid, in tissues.[2][14] One copy of the siRNA target sequence can destroy multiple complementary transthyretin mRNA. 

Pharmacodynamics

The pharmacodynamic effects have been evaluated in patients suffering from hATTR amyloidosis and on treatment with 0.3 mg/kg of patisiran, administered intravenously through infusion every three weeks. The mean reduction of serum TTR was approximately 80% within ten days to 2 weeks after a single dosage. Chronic dosing every three weeks, mean serum TTR decreased by 83% and 84% after 9 and 18 months of treatment, respectively.

The mean maximum reduction in serum TTR over one and a half years was 88%. Serial TTR reductions were comparable regardless of the demographic characteristics of age, sex, race (Caucasian or non-Caucasian), weight, type of TTR mutation, mild to moderate hepatic dysfunction, and mild hepatic impairment.[15]

 Knockdown of TTR remained stable for a minimum of 2 years.[2] In a dose-ranging study, the recommended dosing regimen of 0.3 mg/kg every three weeks proved superior to 0.3 mg/kg every three weeks in maintaining more TTR reduction over the dosing interval.   

Pharmacokinetics

Following administration of a single dosage via intravenous route, systemic exposure to patisiran rises linearly, directly proportional to the dosage, over the dosage range of 0.01 to 0.5 mg per kg. The drug is stable in blood circulation, with more than 95% of the dosage remaining enclosed in lipid nanoparticles.[2]

When patisiran is given at the recommended dosing regimen of 0.3 mg/kg every three weeks, it achieves a steady state within 24 weeks of therapy. The estimated mean +/- SD area under the curve (AUC), Ctrough (trough concentrations), and steady-state peak concentrations (Cmax) were 184 +/- 159 µg·h/mL, 0.021 +/- 0.044 µg/mL, and 7.15 +/- 2.14 µg/mL, respectively.[2]

Compared to the first dose, the accumulation of AUC was 3.2-fold at a steady-state and is attributable to the association of patisiran with the lipid DLin-MC3-DMA.[18] A noticeable accumulation of PEG-C-DMG did not occur. In the placebo-controlled clinical trial, inter-patient variability in exposure to patisiran did not result in any differences in clinical efficacy (change in the modified Neuropathy Impairment Score +7 (mNIS+7) from baseline) or safety parameters (adverse events, serious adverse events).

Distribution

Plasma protein binding of patisiran is low, with 2.1% or less binding with human serum albumin and human α1-acid glycoprotein observed in vitro. The primary site for patisiran distribution is the liver, the principal organ for TTR production. The (mean +/- SD) value for the steady-state volume of distribution (Vss) was 0.26 +/- 0.20 L/kg with chronic therapy using the recommended dosing regimen of 0.3 mg/kg every three weeks.

Elimination

Metabolism

Patisiran metabolizes by the enzymes called ribonucleases into oligonucleotide chains of various lengths and individual nucleotides, similar to endogenous RNA.[2] Patisiran is cleared from the body mainly through metabolism. The mean(+/- SD) terminal elimination half-life of patisiran is 3.2 (+/- 1.8) days, and the mean(+/- SD) total body clearance at steady state (Cass) is 3.0 (+/- 2.5) mL/h/kg.[18] 

Excretion

Less than 1% of the patisiran dosage administered through intravenous infusion is excreted unchanged into urine.[2][18]  

Specific Populations

Age, sex, and race (non-Caucasian vs. Caucasian) did not impact the patisiran pharmacokinetics at a steady-state or TTR reduction. According to population pharmacokinetic and pharmacodynamic analyses, mild or moderate renal dysfunction (eGFR ≥30 to <90 mL/min/1.73m) or mild hepatic impairment (bilirubin >1.0 to 1.5 x ULN alone, or both bilirubin ≤1 x ULN and AST >1 x ULN,) had no impact on patisiran exposure or reduction of TTR burden.[18]

No data exist to inform about the patisiran use in patients with severe or end-stage renal disease, moderate or severe degree of hepatic impairment, and patients who have received prior liver transplant treatment.

Drug Interaction Studies

No formal clinical studies have performed to learn about drug-to-drug interactions were not formally studies. The components of commercially available patisiran are not inducers or inhibitors of cytochrome P-450(CYP) enzymes or transporters at clinically relevant concentrations in plasma. Patisiran is not a substrate of CYP-450 enzymes.

The population pharmacokinetic analysis revealed that concomitant use of moderate or potent CYP3A inhibitors and inducers did not affect the pharmacokinetic parameters of patisiran. Patisiran is unanticipated to interact with other drugs or be impacted by inducers or inhibitors of cytochrome P450 enzymes.

Serum transthyretin (TTR) binds the retinol-binding protein that carries vitamin-A in the plasma. Hence, TTR plays a physiological role in transporting vitamin-A to the liver. In the absence of normal TTR, transportation of vitamin-A will be disabled.[19] The Mean reductions of 45% in serum retinol-binding protein and 62% in serum vitamin A observed over one and a half years.

Efficacy Analysis

In indirect comparisons, the research indicates patisiran has greater therapeutic efficacy than tafamidis and inotersen on neuropathy and Quality of Life (QoL) in patients with polyneuropathy associated with hATTR amyloidosis.[20][21]

Use and Risk Summary in Specific Populations

Pregnancy: There is a pregnancy exposure registry for monitoring outcomes in women with a history of patisiran exposure during the pregnancy. Motivate the physicians to enroll the pregnant females in the registry. Encourage pregnant patients also to register themselves in the program.

The clinical trials have not been conducted on pregnant women to know the patisiran-associated adverse developmental outcomes. Patisiran therapy leads to a reduction in serum vitamin-A levels, and therefore, pregnant patients on patisiran will take vitamin-A supplements daily. Vitamin-A is an essential nutrient for the normal development of the embryo and fetus.

However, excessive vitamin A, also known as hypervitaminosis, is associated with congenital malformations.[22] The effects of decreased maternal serum TTR levels caused by patisiran and vitamin-A supplementation on embryo-fetal development are unknown.

In preclinical studies, intravenous administration of patisiran-LC (lipid complex) to pregnant rabbit females during organogenesis resulted in developmental toxicity such as embryofetal mortality and low fetal body weight at mid and high dosages. These dosages were also associated with toxicity in mothers. Low dosages had no negative impact on fertility or embryo-fetal development. Studies in rats revealed no adverse developmental effects in offspring when patisiran-LC or a pharmacologically active and rodent-specific surrogate were administered intravenously to pregnant and lactating females.

For the general population in the USA, the estimated background risk of miscarriage and the major congenital malformations in clinically confirmed pregnancies are 15 to 20% and 2 to 4%, respectively. The background risk of miscarriage and the significant birth deformities is unknown for the indicated population.

Lactation: There is no scientific data on the secretion of patisiran in human milk, the effects on the nursing infant, or the effects on lactogenesis. While prescribing the patisiran to a lactating mother, consider the developmental and overall health benefits of breastfeeding together with the maternal need for therapy and any potential detrimental effects of patisiran or underlying mother's medical condition on the breastfeeding infant.

Pediatric Use: There is no information on the safety and effectiveness of patisiran in pediatric patients.

Geriatric Use: Dose adjustment is unnecessary for patients 65 years and older. A total of 62 patients aged 65 years and younger, including nine patients aged 75 years and older, received patisiran treatment in the placebo-controlled study. There were no notable differences in safety or effectiveness between these age groups and younger patients. However, some older individuals appear to have more sensitivity to patisiran.

Hepatic Impairment: No dose adjustment is necessary for patients with mild hepatic impairment (bilirubin >1.0 to 1.5 x ULN alone or both bilirubin ≤1 x ULN and AST >1 x ULN). The research data for patisiran use in patients with moderate to severe hepatic impairment does not exist.

Renal Impairment: No dose adjustment is essential in patients suffering from mild or moderate renal impairment with an estimated glomerular filtration rate [eGFR] in the 30 to less than 90 mL/min/1.73m of range. The research data for patisiran use in patients suffering from severe renal dysfunction or end-stage renal disease does not exist.

Administration

Dosage Form and Strength

In the market, patisiran, the disease-modifying drug, is currently available as a lipid complex injection formulation containing 10 mg/5 mL (2 mg per mL) solution in a single dosage glass vial for intravenous infusion. The patisiran solution is sterile and free of preservatives and appears white to off-white, opalescent, and homogeneous. The stopper of the vial does not contain natural rubber latex. Patisiran is available in a carton package containing a single-dose vial. 

Dosage and Administration

Dosing Information

The licensed healthcare practitioners prescribe patisiran to the patients. Only qualified healthcare professionals are permitted to administer the patisiran. Patisiran has injected via intravenous (IV) infusion. Its dose is calculated based on the patient’s actual body weight. The recommended dosage for patients weighing less than 100 kg is 0.3mg per kg body weight once every three weeks. The recommended dose is 30 mg once every three weeks for patients weighing 100 kg or more.[1]

Missed Dose

If an infusion misses for any reason, administer the dose of patisiran as soon as possible. If patisiran administration resumes within three days of the missed dosage, follow the patient’s original schedule for subsequent dosing. If you administer patisiran greater than three days after the missed dosage, then, from this last dosage, continue dosing every three weeks henceforth.

Required Premedication

All patients receive premedication routinely before administration of patisiran dosage to decrease the risk of Infusion Related Reactions (IRR). Each of the premedication regimen components is administered on the day of patisiran therapy at least one hour before the start of infusion.[23]

The premedication regimen consists of intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent), intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent), intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent), and oral acetaminophen (500 mg).[2]

Patients must take each of the premedications. If any premedications are unavailable or intolerable via intravenous route, administer equivalents orally. If patients develop symptoms or signs of infusion-related reactions, administer additional doses of one or more of the premedications.

If patients tolerate patisiran well but experience adverse reactions related to corticosteroids, then corticosteroids may be decreased by 2.5 mg increments to a minimum of intravenously administered 5 mg dexamethasone or equivalent. Patients with a known history of infusion-related reactions may need higher or additional doses of premedications before subsequent infusions.

Preparation Instructions

Patisiran must be filtered and diluted before administration through intravenous infusion. The pharmacist or other healthcare professional should dilute the patisiran solution using strict sterile techniques as follows:

• Firstly, remove the vial of patisiran from the refrigerator and allow it to warm up to room temperature. Do not shake or vortex the vial.
• Visually inspect for any discoloration and particulate matter. Do not use the medicine if any discoloration or foreign particles are present. Normal patisiran is a white to off-white and opalescent homogeneous solution. In addition, a coating, white to off-white, may be seen on the inner surface of the vial, usually at the liquid-headspace interface. The quality of the product is not affected by the presence of white to off-white coating.
• Compute the required dosage of patisiran according to the recommended weight-based dose.
• Withdraw the complete contents from one or more patisiran vials into the single sterile syringe. Then, filter the patisiran using a 0.45-micron polyethersulfone (PES) syringe filter. Filter patisiran directly into a container, either a sterile glass vial or syringe.
• Withdraw the required volume of filtered patisiran from the sterile container (glass vial) into the single sterile syringe.
• Then, for dilution, transfer the patisiran from the syringe into an infusion bag containing Normal saline injection, USP, to make 200mL of volume. Do not use any other intravenous diluent to prepare diluted patisiran solution.
• Gently invert the bag containing a diluted solution of patisiran to mix entirely. Do not shake the infusion bag. Do not mix with other drugs.
• Patisiran does not contain preservatives. Therefore, after dilution, the immediate use of the patisiran is recommended. The infusion bag of diluted patisiran can be stored at room temperature, up to 86*F (30*C), for up to 16 hours, including 80 minutes of infusion time. Do not freeze.
• Discard any unused portion of the patisiran in the vial. 

Infusion Instructions

• Use a dedicated intravenous line with an infusion set containing a 1.2-micron polyethersulfone (PES) in-line infusion filter. Use an infusion set that is free of DEHP.
• Infuse the diluted solution of patisiran intravenously through an ambulatory infusion pump for approximately 80 minutes, at about 1 mL/min of infusion rate for the first 15 minutes, and escalate to about 3 mL/min for the remaining portion of the infusion.[1] If the patient develops the IRRs, prolong the duration of patisiran administration. 
• Administer the patisiran only through a venous access line that is free-flowing. Monitoring of the infusion site for possible extravasation is required and as per the local standard practice for non-vesicants, manage any suspected infiltration.
• Routinely monitor the patient during the patisiran infusion and the post-infusion whenever clinically indicated.
• After the infusion is complete, flush the intravenous administration set using 0.9% sodium chloride (normal saline) Injection (USP) to deliver the entire drug dose. 

Storage and Handling

Patisiran needs specific storage conditions. Store it at 36 F to 46 F (2 C to 8 C). Do not freeze; discard the vial if it has been frozen. Patisiran can be stored at room temperature up to 77 F (up to 25 C) for two weeks if refrigeration is unavailable. The infusion bag containing diluted patisiran solution can be stored at room temperature, up to 86 F (30 C), for up to 16 hours, including 80 minutes of infusion time. 

Adverse Effects

Patisiran, a first-in-class siRNA molecule, is administered as a drip into the vein.[2][24] The scientific data from the clinical trials have revealed that patisiran has an overall acceptable safety profile, only most frequently reported adverse events are upper respiratory tract infections and infusion-related reactions (IRRs).[2][25] 

Dyspepsia, dyspnea, muscle spasms, arthralgia, erythema, bronchitis, and vertigo are the other adverse reactions from the placebo-controlled clinical trial that occurred in at least 5% of patients in the patisiran-treated group and at least 3% more frequently than in patients in the placebo-treated group.

Infusion-related reactions have occurred in patients treated with patisiran. In clinical trials, all subjects received premedication with acetaminophen, corticosteroid, and antihistamines (H1 and H2 receptor blockers) to decrease the risk of IRRs.[26]

In a randomized controlled clinical study, 19% of patients treated with patisiran experienced IRRs, compared to 9% of patients who received a placebo. Among patisiran-treated subjects who experienced an IRR, the majority (79%) experienced the first episode of IRR within the first two infusion therapy. The frequency of IRRs decreased over time.

The incidents of IRRs resulted in interruption of infusion in 5% of patients and permanent discontinuation of patisiran in 0.7% of subjects (one patient) in clinical studies. The flushing (including facial erythema or skin warm), headache, back pain, nausea, abdominal pain, and dyspnea were the most common symptoms of patisiran IRRs affecting more than 2% of patients across clinical trials.[26][27]

Other manifestations included but were not limited to arthralgia or pain (including neck and musculoskeletal pain), chills, cough, chest pain or chest discomfort, rash, increased heart rate or palpitations, hypotension, hypertension, dizziness, fatigue, and facial edema. Severe hypotension, syncope, and pruritus as symptoms of IRRs reported from the expanded access program (EAP) and postmarketing setting.

On the day of patisiran therapy, premedication is administered at least 60 minutes before initiating the infusion to prevent IRRs.[23] Patients need close monitoring for symptoms and signs of IRRs during infusion therapy. If any symptoms or signs of IRRs occur, immediately consider slowing or interrupting the infusion and institute the medical management as clinically indicated, such as corticosteroids or other symptomatic treatment. When symptoms completely resolve, patisiran infusion resumes at a slow rate if it is interrupted. In severe or life-threatening reactions, patisiran treatment needs to discontinue permanently.

During subsequent infusions for the patients who have experienced the IRRs, higher or additional dosages of premedication and slower infusion rate might help reduce the risk of infusion-related reactions(IRRs).  

The patisiran tends to reduce levels of serum vitamin-A. Therefore, vitamin-A supplementation at recommended daily allowance is advisable to prevent its deficiency when the patient is on patisiran treatment.[2] It is crucial not to supplement with a higher vitamin-A dosage than the recommended daily allowance to achieve normal serum levels as they do not reflect the total vitamin-A content of the body. If a patient develops the ocular manifestations suggestive of vitamin-A deficiency, such as night blindness, etc., during patisiran therapy, referral to the ophthalmologist is required.

Four serious adverse events of atrioventricular (AV) heart block (2.7%), including three cases of complete AV block, were reported in patients treated with patisiran. No such AV-block (AEs, or SAEs) occurred in placebo-treated patients. The first-degree heart block and Mobitz’s type-1 second-degree heart block require only clinical monitoring and observation. The patients with Mobitz type-2 second-degree heart block and complete heart block require a permanent pacemaker.

Ocular adverse events (AEs) occurred in 2 to less than 5% of patients treated with patisiran and more frequently than patients in the placebo group in the randomized clinical trial, including dry eyes, the most common (5% vs. 3%), followed by blurred vision (3% vs.1%), and vitreous floaters, the least common (2% vs. 1%). 

Extravasation occurred in less than 0.5% of patisiran infusions in clinical trials, including cases graded and reported the serious. Symptoms and signs included erythema or injection site redness, infusion or injection site swelling, burning sensation or injection site pain, phlebitis or thrombophlebitis, dermatitis (subcutaneous inflammation), and cellulitis.[26][28][29]

The risk of injection or infusion site cellulitis reduces by strict aseptic and antiseptic precautions. The most common microorganism responsible for non-purulent cellulitis is Group A beta-hemolytic streptococci and staphylococcus aureus for purulent cellulitis. The patient management strategy includes antibiotics and supportive therapy. Penicillin is the treatment of choice. If the patient has a history of penicillin allergy, cephalexin can cause cross hypersensitivity and, therefore, in that case, clindamycin is the treatment of choice.

Immunogenicity

In the clinical trials, the incidence of developing anti-patisiran antibodies was low (3.4%) and transient, without effects on pharmacokinetics, pharmacodynamics, efficacy, or safety.[15]

Contraindications

Patisiran is contraindicated only in managing patients with a known history of severe or life-threatening patisiran infusion-related reactions.

Monitoring

Patients should be monitored for symptoms and signs of infusion-related reactions (IRRs) during patisiran infusion and post-infusion if indicated. In practice, routine monitoring of plasma patisiran or vitamin-A levels does not require. Healthcare providers perform a thorough clinical assessment of patients before initiating therapy and follow-up visits to assess therapeutic efficacy and ensure patient safety.

The patients will need counseling regarding the following health-related conditions:

Infusion-related Reactions

Provide patients with information regarding the symptoms and signs of infusion-related reactions (e.g., flushing, dyspnea, facial edema, rash, chest pain, syncope, increased heart rate). Instruct the patients to immediately reach out to their healthcare providers if they experience any clinical manifestations of infusion-related reactions.

Recommended Vitamin A Supplementation

Inform patients that patisiran therapy decreases serum vitamin A levels. Advise patients to take the vitamin A supplement at recommended daily allowance regularly.[2] Counsel the patients to consult their healthcare provider if they suffer ocular symptoms (e.g., night blindness) indicating vitamin A deficiency. In addition, refer the patients to an ophthalmologist if they experience these symptoms.[19]

Pregnancy

Recommend the patients to inform their healthcare provider if they are pregnant or planning to conceive while on patisiran. Inform the females of childbearing age about the potential adverse effects on the fetus. If the patients become pregnant while on therapy, encourage them to enroll in the patisiran pregnancy exposure registry.

Toxicity

Patisiran is a well-tolerated medicine and has demonstrated long-term safety and efficacy.[27][30] Its nonclinical toxicity (carcinogenesis, mutagenesis, impairment of fertility) is as below:

Carcinogenesis

In animal studies, patisiran was negative for carcinogenicity when administered intravenously in TgRasH2 type of mice for 26 weeks at dosages of 0.5, 2, or 6 mg per kg every two weeks.

Mutagenesis

Patisiran-LC was not genotoxic in vitro (bacterial mutagenicity assay and human peripheral blood lymphocytes chromosomal aberration assay) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

The administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or pharmacologically active and rodent-specific surrogate (0.1 mg/kg) to male rats via intravenous route every two weeks before and throughout mating to untreated females resulted in no any adverse effects on the fertility.

The administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or pharmacologically active and rodent-specific surrogate (1.5 mg/kg) to female rates via intravenous route every week for two weeks before and continuing throughout the organogenesis produced no adverse effects on the reproduction or development of the embryo and fetus.

Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or sperm morphology or count.

Enhancing Healthcare Team Outcomes

Patisiran, a liposomal siRNA molecule, is used to treat patients with polyneuropathy (sensorimotor and autonomic neuropathy) and cardiomyopathy associated with hereditary transthyretin-mediated amyloidosis and wild-type transthyretin-mediated amyloidosis (ATTRwt).[8][31] The healthcare providers prescribe the patisiran but the proper management of the patients requires open communication and collaboration among all healthcare team members.

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, multisystem, progressive, and life-threatening disease affecting adults. Therefore, high awareness among healthcare providers is essential in making an early diagnosis and initiating prompt patisiran treatment. Providers educate the patients regarding the adverse effects of patisiran and health conditions requiring immediate consultation with health providers. They also evaluate the efficacy and safety of the patisiran at each follow-up visit. They also refer the patients with ocular symptoms suggestive of vitamin-A deficiency to an ophthalmologist. They encourage pregnant patients to enroll in the pregnancy monitoring registry. 

Patisiran infusion can be administered in the clinician's office, infusion center, or home by a qualified health care professional. Pharmacists will verify the drug dosage and administration schedule to ensure patients get the right amount of medicine at the proper intervals. Pharmacists can advise the team members and patients on appropriately storing the medication.

Patients must be highly compliant with the medicine to halt the progress of their medical condition. They will immediately contact their healthcare providers upon experiencing adverse reactions. They need to take vitamin A supplements regularly at recommended daily allowance. In addition, patients could join support groups and advocacy organizations to cope with their emotions. The caregivers will learn about the natural course of the disease to have realistic expectations in the loved one's amyloidosis journey.

Caregivers can utilize the available resources to get assistance to avoid burnout. All team members are responsible for accurately documenting the patient's status and reporting any concerns to the rest of the team, so therapeutic interventions can occur if necessary. Thus, an interprofessional team approach is essential to achieve optimal therapeutic goals. [Level 5]