Piasky (Crovalimab)

What Is Piasky and What Is It Used For?

Quick Answer: Piasky (crovalimab) is a complement C5 inhibitor monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria (PNH) in adults and adolescents aged 12 and older weighing at least 40 kg. It prevents the immune system from destroying red blood cells, thereby reducing hemolysis and its associated symptoms.

Piasky contains the active substance crovalimab, a humanized monoclonal antibody — a type of protein engineered to bind to a specific target in the body. Crovalimab belongs to a class of medications known as complement inhibitors that target complement protein C5, a critical component of the immune system's complement pathway.

Piasky is approved for treating paroxysmal nocturnal hemoglobinuria (PNH), a rare and serious blood disorder in which the body's immune system mistakenly attacks and destroys its own red blood cells. This process, called complement-mediated hemolysis, occurs because red blood cells in PNH patients lack protective surface proteins that normally shield them from complement activation. PNH affects approximately 1–2 people per million worldwide, with onset typically occurring in adulthood.

Piasky is indicated for patients who have hemolysis (breakdown of red blood cells) with clinical symptoms suggesting high disease activity, as well as patients whose disease is clinically stable following treatment with a complement C5 inhibitor for at least the preceding six months. The medication is approved for adults and adolescents aged 12 years and older who weigh at least 40 kg.

Symptoms of PNH That Piasky Treats

Complement-mediated hemolysis in PNH can lead to a wide range of debilitating symptoms that significantly impact quality of life. By blocking complement activation, Piasky helps reduce or resolve these manifestations:

• Anemia symptoms — fatigue, weakness, shortness of breath, and reduced exercise tolerance caused by low red blood cell counts
• Dark or reddish urine (hemoglobinuria) — a hallmark sign of PNH caused by free hemoglobin released from destroyed red blood cells
• Abdominal pain — smooth muscle dystonia and microvascular thrombosis triggered by free hemoglobin scavenging nitric oxide
• Dysphagia (difficulty swallowing) — esophageal spasm related to nitric oxide depletion
• Erectile dysfunction — also caused by impaired nitric oxide signaling
• Kidney damage — chronic hemolysis can lead to progressive renal impairment through hemoglobin-mediated tubular injury
• Thrombosis (blood clots) — PNH patients have a significantly elevated risk of both venous and arterial thrombotic events, which represent the leading cause of morbidity and mortality in PNH
• Transfusion dependence — many PNH patients require regular blood transfusions to manage severe anemia

How Piasky Works

Crovalimab, the active substance in Piasky, binds to complement protein C5, which is a central component of the body's innate immune defense known as the complement system. Under normal circumstances, the complement system helps the body fight infections by forming the membrane attack complex (MAC, also called C5b-9) on the surface of invading microorganisms. However, in PNH patients, this same process attacks the patient's own red blood cells because they lack the protective complement-regulating proteins CD55 and CD59.

By binding to C5, crovalimab prevents its cleavage into C5a (a potent pro-inflammatory mediator) and C5b (the initiating component of the MAC). This blocks the formation of the MAC on red blood cell surfaces, thereby halting complement-mediated intravascular hemolysis. The result is a reduction in red blood cell destruction, improved hemoglobin levels, decreased lactate dehydrogenase (LDH) levels (a marker of hemolysis), and reduced need for blood transfusions.

A distinctive feature of crovalimab is its recycling antibody technology. Unlike conventional monoclonal antibodies that are eliminated along with their target, crovalimab is designed to release C5 within the acidic environment of endosomes after cellular uptake. The antibody is then recycled back to the cell surface where it can bind another C5 molecule, while the released C5 is directed to lysosomes for degradation. This pH-dependent binding mechanism allows crovalimab to achieve sustained C5 inhibition with less frequent dosing compared to earlier-generation C5 inhibitors, enabling maintenance treatment every four weeks.

What Should You Know Before Taking Piasky?

Quick Answer: Before starting Piasky, you must be vaccinated against meningococcal infection at least 2 weeks prior. Do not use Piasky if you are allergic to crovalimab, have an active meningococcal infection, or are unvaccinated without antibiotic cover. Inform your doctor about all medications, especially other complement inhibitors.

Contraindications

Piasky must not be used in the following situations:

• Allergy to crovalimab or any excipient — if you are allergic to any of the ingredients in Piasky (including histidine, aspartic acid, arginine hydrochloride, poloxamer 188, or water for injections), do not use this medication
• Active meningococcal infection — if you currently have a meningococcal infection (a serious bacterial infection caused by Neisseria meningitidis that can affect the brain membranes, spinal cord, and bloodstream)
• Unvaccinated against meningococcal disease — unless you are receiving prophylactic antibiotic treatment until at least 2 weeks after receiving the meningococcal vaccination

Warnings and Precautions

Before starting Piasky, your doctor will ensure your meningococcal vaccination is current. You must be fully vaccinated at least 2 weeks before your first dose. Even if you were vaccinated as a child, your doctor may determine that revaccination is needed. If Piasky is urgently needed before full vaccination can take effect, your doctor will prescribe prophylactic antibiotics from the start of treatment until at least 2 weeks after vaccination.

Seek immediate medical attention if you experience any of the following symptoms, which may indicate a meningococcal infection:

• Fever (high temperature)
• Nausea or vomiting
• Severe headache
• Confusion or irritability
• Stiff neck or back
• Muscle aches with flu-like symptoms
• Sensitivity to light (photophobia)
• Skin rash or petechiae (small purple or red spots on the skin)

Your doctor will provide you with a Patient Safety Card listing the warning signs of meningococcal infection and sepsis. You must carry this card at all times during treatment and for 11 months after your last dose of Piasky. Show this card to any healthcare professional you visit, especially in emergency situations.

Other Serious Infections

Piasky may also increase the risk of other serious infections, particularly those caused by Streptococcus pneumoniae (pneumococcal disease) and Haemophilus influenzae. Your doctor should ensure your vaccinations against these organisms are up to date at least 2 weeks before starting treatment. Be alert for and report symptoms of infection, including:

• Fever or chills
• Cough or chest pain
• Fatigue or weakness
• Shortness of breath
• Painful skin rash
• Sore throat
• Burning pain during urination
• General feeling of being unwell

Switching from Another C5 Inhibitor

If you are switching to Piasky from another C5 complement inhibitor (such as eculizumab or ravulizumab), inform your doctor. During the first 30 days after switching, you may experience a temporary type III immune complex reaction. This occurs when antibodies from the previous treatment and crovalimab simultaneously bind to C5, forming immune complexes. Symptoms may include:

• Joint pain or musculoskeletal problems
• Numbness, tingling, or pins-and-needles sensations, particularly in the hands and feet
• Rash or other skin problems
• Fever

This reaction is generally self-limiting and resolves as immune complexes are cleared from the body. However, report any of these symptoms to your doctor promptly.

Infusion and Injection Reactions

Both the intravenous infusion (first dose) and subcutaneous injections may cause local or systemic reactions. Signs to watch for include headache, lower back pain, pain at the infusion or injection site, swelling, bruising, redness, itching, and rash. In rare cases, more severe allergic reactions may occur, with symptoms such as chest tightness, wheezing, shortness of breath, fever or chills, severe dizziness, facial or lip swelling, and hives. If you experience any signs of a severe allergic reaction, seek immediate medical attention.

Stopping Piasky

If you stop taking Piasky without switching to another PNH treatment, the protective effect against complement-mediated hemolysis will gradually wear off. You may experience a return or worsening of PNH symptoms, including severe hemolysis (which may be worse than before treatment), dark urine, abdominal pain, fatigue, kidney problems, difficulty swallowing, erectile dysfunction, and blood clots. Do not stop Piasky without discussing it with your doctor first, as careful monitoring and a transition plan may be necessary.

Pregnancy and Breastfeeding

There is limited data on the use of Piasky during pregnancy, and potential effects on the developing fetus are unknown. As a monoclonal antibody (IgG), crovalimab is expected to cross the placental barrier, particularly during the second and third trimesters. Your doctor will carefully weigh the potential risks and benefits before recommending Piasky during pregnancy.

It is not known whether crovalimab is excreted in human breast milk, although given its properties as an IgG antibody, excretion into milk is expected. Your doctor will discuss the potential risks of using Piasky while breastfeeding. The decision to discontinue breastfeeding or to discontinue treatment should take into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Children and Adolescents

Piasky is not approved for children under 12 years of age or for children weighing less than 40 kg, as the medication has not been studied in these populations. For adolescents aged 12 and older weighing at least 40 kg, the same dosing regimen as for adults applies.

Driving and Operating Machinery

Piasky has no or negligible effect on the ability to drive vehicles or operate machinery.

How Does Piasky Interact with Other Drugs?

Quick Answer: No clinically significant drug-drug interactions have been identified for Piasky. However, patients switching from or to another C5 complement inhibitor require careful management due to the risk of type III immune complex reactions and potential gaps in complement inhibition.

Crovalimab is a monoclonal antibody that is not metabolized by cytochrome P450 enzymes or other common drug-metabolizing pathways. Instead, it is degraded through normal catabolic pathways into amino acids, similar to endogenous immunoglobulins. As a result, pharmacokinetic drug-drug interactions with conventional small-molecule medications are not expected.

However, there are important considerations regarding the use of Piasky in combination with or when switching between other complement-targeting therapies. Inform your healthcare provider about all medications you are currently taking, have recently taken, or plan to take.

It is important to note that because Piasky inhibits complement activation, the immune response to certain vaccine types (particularly capsular polysaccharide vaccines) may theoretically be reduced. Discuss the timing of any planned vaccinations with your healthcare provider.

What Is the Correct Dosage of Piasky?

Quick Answer: Piasky dosing is weight-based. The first dose is given intravenously, followed by subcutaneous loading doses on days 2, 8, 15, and 22, and then maintenance doses every 4 weeks from day 29 onward. Patients weighing 40–99 kg receive 680 mg maintenance doses; patients weighing 100 kg or more receive 1,020 mg maintenance doses.

Always use Piasky exactly as your doctor has prescribed. Before starting treatment, you must have received meningococcal vaccination at least 2 weeks prior (or be receiving prophylactic antibiotics if vaccination was given less than 2 weeks before).

Adults and Adolescents (12 years and older, weighing 40 kg or more)

Piasky follows a loading dose plus maintenance dose regimen. The first dose is always administered as an intravenous infusion by a healthcare professional. Subsequent doses are given as subcutaneous injections. After proper training, you or your caregiver may administer the subcutaneous maintenance doses at home.

If you are switching from another C5 inhibitor, the first loading dose of Piasky should be given on the date when the next scheduled dose of your previous medication was due.

Your maintenance dose may be adjusted if your body weight changes significantly during treatment. Inform your doctor if your weight crosses the 100 kg threshold in either direction, as this will affect your dosing regimen.

Children

Piasky is not approved for use in children under 12 years of age or in children weighing less than 40 kg. Clinical studies have not been conducted in these populations. For adolescents aged 12 years and older weighing at least 40 kg, the adult dosing regimen applies.

Elderly Patients

No dose adjustment is required for elderly patients. Clinical trials included patients across a wide age range, and no clinically meaningful differences in safety or efficacy were observed in older adults. However, as with all medications, elderly patients may be more susceptible to infections, and careful monitoring is advised.

Missed Dose

Adherence to the prescribed dosing schedule is essential for maintaining effective complement inhibition and preventing breakthrough hemolysis. If you miss a dose or part of a dose:

• Administer the missed dose (or the missed portion) as soon as possible
• Then resume your regular dosing schedule at the next planned time
• Do not take a double dose to compensate for a missed dose
• If you miss a healthcare appointment for an administered injection, reschedule as soon as possible
• Contact your doctor, pharmacist, or nurse if you are unsure about what to do

Overdose

If you suspect you have used more Piasky than prescribed, contact your doctor, pharmacist, or nurse immediately for advice. There is limited experience with overdose of crovalimab. Given its mechanism of action, an overdose would be expected to result in prolonged and potentially excessive complement inhibition, which could further increase the risk of serious infections. Medical monitoring would be advised.

What Are the Side Effects of Piasky?

Quick Answer: The most common side effects of Piasky include fever, type III immune complex reactions (when switching from another C5 inhibitor), upper respiratory tract infections, infusion reactions, and headache. The most serious risk is meningococcal infection, which can be life-threatening.

Like all medicines, Piasky can cause side effects, although not everyone will experience them. Your doctor will discuss the potential side effects and explain the benefits and risks of Piasky before starting treatment. The frequency categories below are based on clinical trial data.

Immunogenicity

As with all therapeutic monoclonal antibodies, your immune system may produce anti-drug antibodies (ADAs) against crovalimab. The development of neutralizing antibodies could potentially reduce the effectiveness of Piasky or cause it to stop working. If you notice a return of PNH symptoms while on treatment — such as dark urine, increased fatigue, abdominal pain, or signs of blood clots — report these to your doctor immediately, as they may indicate a loss of treatment response that requires investigation.

How Should You Store Piasky?

Quick Answer: Store Piasky in the refrigerator at 2°C–8°C (36°F–46°F). Do not freeze. Unopened vials may be stored at room temperature (up to 30°C/86°F) for a maximum of 7 days total. Filled syringes must be used immediately.

Proper storage of Piasky is essential to maintain its effectiveness and safety. Follow these guidelines carefully:

• Keep out of sight and reach of children
• Do not use after the expiry date printed on the carton and vial label after "EXP." The expiry date refers to the last day of that month
• Store in a refrigerator at 2°C–8°C (36°F–46°F)
• Do not freeze. If accidentally frozen, discard the vial and contact your pharmacist
• Keep in the outer carton to protect from light. Do not expose to direct sunlight once removed from the carton
• Temporary room temperature storage: Unopened vials may be stored at room temperature (up to 30°C/86°F) for a cumulative maximum of 7 days, then returned to the refrigerator. You can tick a box on the inside of the vial carton for each day stored outside the refrigerator. Discard the medicine if it has been stored at room temperature for more than 7 days total
• Do not store filled syringes. Once Piasky is drawn into a syringe, it must be used immediately
• Do not use if the solution is cloudy, discolored, or contains visible particles. Piasky should be a clear, strongly opalescent, and almost colorless to yellowish-brown solution
• Disposal: Do not dispose of unused medicine via wastewater or household waste. Ask your pharmacist about proper disposal methods to protect the environment

What Does Piasky Contain?

Quick Answer: Each Piasky vial contains 340 mg of crovalimab in 2 mL of solution (170 mg/mL). Other ingredients include histidine, aspartic acid, arginine hydrochloride, poloxamer 188, and water for injections.

Active Ingredient

The active substance is crovalimab. Each glass vial contains 340 mg of crovalimab in 2 mL of solution, resulting in a concentration of 170 mg/mL. Crovalimab is a humanized recycling monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.

Inactive Ingredients (Excipients)

• L-Histidine — buffer to maintain appropriate pH
• L-Aspartic acid — stabilizer
• Arginine hydrochloride — stabilizer to prevent protein aggregation
• Poloxamer 188 — surfactant to prevent surface adsorption and aggregation
• Water for injections — solvent

Appearance and Packaging

Piasky is a clear, strongly opalescent, and almost colorless to yellowish-brown solution for injection or infusion. Each pack contains 1 glass vial with 2 mL of solution. The vial has a rubber stopper and an aluminum seal with a flip-off cap.

Marketing Authorization Holder and Manufacturer

Piasky is manufactured by Roche Pharma AG, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. The marketing authorization is held by Roche Registration GmbH at the same address. Additional information about Piasky is available on the European Medicines Agency (EMA) website.