PALYNZIQ SIDE EFFECTS

Last updated on MDtodate: 10/9/2022

SIDE EFFECTS

The following serious adverse reactions are discussed below and in other sections of labeling:

• Anaphylaxis
• Other Hypersensitivity Reactions

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect a total treatment exposure of 789 patient-years in 285 patients who received Palynziq in an induction/titration/maintenance regimen in clinical trials. Of the 285 patients, 229 patients were exposed to Palynziq for 24 weeks, 209 patients were exposed for 1 year, 181 patients were exposed for 2 years, and 160 patients were exposed for 3 years or longer. The patient population was evenly distributed between male and female patients, the mean age was 29 years (range: 16 to 56 years), and 98% of patients were White.

The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, nausea, abdominal pain, vomiting, cough, oropharyngeal pain, pruritus, diarrhea, nasal congestion, fatigue, dizziness, and anxiety.

Of the 285 patients exposed to Palynziq in an induction/titration/maintenance regimen in clinical trials, 44 (15%) patients discontinued treatment due to adverse reactions. The most common adverse reactions leading to treatment discontinuation were hypersensitivity reactions (6% of patients) including anaphylaxis (3% of patients), angioedema (1% of patients), arthralgia (4% of patients), generalized skin reactions lasting at least 14 days (2% of patients), and injection site reactions (1% of patients).

The most common adverse reactions leading to dosage reduction were arthralgia (15% of patients), hypersensitivity reactions (9% of patients), injection site reactions (4% of patients), alopecia (3% of patients), and generalized skin reactions lasting at least 14 days (2% of patients).

The most common adverse reactions leading to temporary drug interruption were hypersensitivity reactions (14% of patients), arthralgia (13% of patients), anaphylaxis (4% of patients), and injection site reactions (4% of patients).

Table 2 lists adverse reactions reported in at least 15% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials, and illustrates the adverse reaction rates over time by treatment phase. Table 3 lists laboratory abnormalities reported in at least 10% of patients treated with Palynziq in an induction/titration/maintenance dosage regimen in clinical trials.

For these analyses, the induction/titration phase was defined as the time prior to reaching a stable dose (completing an 8-week phase at the same dose level). Once a stable dosage was reached, patients were considered to be in the maintenance phase thereafter. Safety data for patients who reached the maintenance phase are included within either the induction/titration or maintenance phases depending on the onset date of the adverse reaction. Safety data for patients who did not reach the maintenance phase are included within the induction/titration phase. The maintenance phase includes data for patients who were previously on Palynziq and transitioned to placebo during the randomized withdrawal period of Study 302.

Rates of adverse reactions (adjusted for duration of exposure) generally decreased over time and for some stayed relatively stable. In the maintenance phase, the rate of adverse reactions (adjusted for duration of exposure) in patients who reached the maintenance phase was comparable across dosages evaluated. The types and rate of adverse reactions reported during the maintenance phase in patients who received 20 mg once daily, 40 mg once daily, and 60 mg once daily were similar. During long-term treatment (greater than 36 months), the exposure-adjusted rates of adverse reactions decreased.

Rates of laboratory abnormalities (adjusted for duration of exposure) stayed relatively stable over time, except for complement C4 below lower limit of normal (LLN) and hs-CRP above 0.287 mg/dL over a 6 month period (both decreased over time) and hypophenylalaninemia (blood phenylalanine concentration below 30 micromol/L) on a single measurement (increased over time). There were no dose-related trends in type or rate of laboratory abnormalities (adjusted for duration of exposure) reported during the maintenance phase in patients receiving 20 mg once daily, 40 mg once daily, or 60 mg once daily.

Table 1: Adverse Reactions* Reported in at least 15% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials – Incidence and Exposure-Adjusted Rates

Treatment Phase Treatment Duration	Induction/Titration Phase (N = 285) 141 person-years Mean: 188 days Median: 116 days Range: 1 to 2266 days		Maintenance Phase (N = 225) 652 person-years Mean: 1087 days Median: 1158 days Range: 5 to 2017 days
Adverse Reaction	N (%)†	Episodes (Rate)†	N (%)†	Episodes (Rate)†
Injection site reactions‡	252 (88%)	2965 (21)	166 (74%)	2169 (3.3)
Arthralgia§	211 (74%)	1049 (7.4)	154 (68%)	893 (1.4)
Hypersensitivity reactions¶	153 (54%)	634 (4.5)	145 (64%)	845 (1.3)
Headache#	102 (36%)	214 (1.5)	126 (56%)	1049 (1.6)
Generalized skin reaction lasting at least 14 daysÞ	61 (21%)	97 (0.7)	93 (41%)	186 (0.3)
Nausea	52 (18%)	68 (0.5)	69 (31%)	141 (0.2)
Abdominal painβ	39 (14%)	54 (0.4)	67 (30%)	162 (0.3)
Vomiting	36 (13%)	53 (0.4)	68 (30%)	139 (0.2)
Cough	27 (9%)	33 (0.2)	67 (30%)	100 (0.2)
Oropharyngeal pain	38 (13%)	45 (0.3)	65 (29%)	108 (0.2)
Pruritus	58 (20%)	102 (0.7)	61 (27%)	424 (0.7)
Diarrhea	26 (9%)	32 (0.2)	61 (27%)	116 (0.2)
Nasal congestion	12 (4%)	16 (0.1)	61 (27%)	87 (0.1)
Fatigue	37 (13%)	81 (0.6)	55 (24%)	110 (0.2)
Dizziness	47 (16%)	65 (0.5)	48 (21%)	100 (0.2)
Anxiety	14 (5%)	23 (0.2)	48 (21%)	100 (0.2)
Alopecia	13 (5%)	14 (0.1)	43 (19%)	62 (0.1)
* ≥ 15% incidence in either treatment phase † N (%) = Number of patients with at least 1 Adverse Reaction (%); Rate = Exposure-Adjusted Rate of Adverse Reactions (Adverse Reactions/Person-Years) ‡ Includes injection site: reaction, erythema, pruritus, pain, bruising, rash, swelling, urticaria, induration, hemorrhage, edema, mass, inflammation, nodule, discoloration, warmth, hematoma, irritation, vesicles, hypersensitivity, papule, discomfort, scar, paresthesia, hypertrophy, extravasation, dryness, scab § Includes arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain ¶ Includes rash, urticaria, anaphylaxis, rash generalized, hypersensitivity, rash erythematous, rash maculo-papular, rash pruritic, serum sickness, swelling face, dermatitis contact, swollen tongue, lip swelling, rash macular, pharyngeal edema, injection site hypersensitivity, eczema, drug eruption, dermatitis allergic, dermatitis, tongue edema, palatal edema, edema mouth, multiple allergies, lip edema, eye edema, exfoliative rash, drug hypersensitivity, dermatitis atopic, dermatitis acneiform, pruritus allergic, mouth swelling, implant site rash, gingival swelling, face edema, eyelid edema, eye swelling, dermatitis psoriasiform, dermatitis infected, conjunctivitis allergic, bronchospasm, angioedema, allergic sinusitis, allergic cough, eczema nummular, rhinitis allergic # Includes headache, migraine, sinus headache Þ Includes pruritus, rash, urticaria, dry skin, rash erythematous, erythema, cellulitis, rash macular, pruritus generalized, petechiae, dermatitis allergic, skin infection, skin induration, rash maculo-papular, rash generalized, pharyngeal edema, macule, granulomatous dermatitis, exfoliative rash, drug eruption, dermatitis atopic, dermatitis, xanthogranuloma, skin plaque, skin mass, skin lesion, skin hypopigmentation, skin hyperpigmentation, skin exfoliation, septal panniculitis, scar, rash pruritic, rash papular, psoriatic arthropathy, pruritus allergic, papule, necrobiosis lipoidica diabeticorum, furuncle, eczema, ecchymosis, dermatitis psoriasiform, dermatitis infected, blister, eczema nummular, granuloma, infected dermal cyst, lipohypertrophy, psoriasis, skin irritation β Includes abdominal pain, abdominal pain upper, abdominal discomfort

 

Table 2: Laboratory Abnormalities Reported in at least 10% of PKU Patients Treated with Palynziq in an Induction/Titration/Maintenance Regimen in Clinical Trials – Incidence and Exposure-Adjusted Rates

Treatment Phase Treatment Duration	Induction/Titration Phase (N = 285) 141 person-years Mean: 188 days Median: 116 days Range: 1 to 2266 days		Maintenance Phase (N = 225) 652 person-years Mean: 1087 days Median: 1158 days Range: 5 to 2017 days
Laboratory Measurement	N (%)*	Episodes (Rate)*	N (%)*	Episodes (Rate)*
Complement factor C3 below LLN	195 (68%)	453 (3.2)	188 (84%)	2259 (3.5)
C-reactive protein (CRP) above ULN	182 (64%)	359 (2.5)	160 (71%)	1414 (2.2)
Hypophenylalaninemia† on a single measurement	53 (19%)	216 (1.5)	147(65 %)	1553 (2.4)
Complement factor C4 below LLN	177 (62%)	318 (2.3)	111 (49%)	714 (1.1)
Hypophenylalaninemia† on 2 or more consecutive measurements	45 (16%)	62 (0.4)	111 (49%)	204 (0.3)
Blood creatine phosphokinase (CPK) above ULN	50 (18%)	88 (0.6)	108 (48%)	377 (0.6)
Hs-CRP above 0.287 mg/dL over a 6 month period	34 (12%)	34 (0.4)	36 (16%)	46 (0.1)
* N (%) = Number of patients with at least 1 laboratory abnormality (%); Rate = Exposure-Adjusted Rate of Laboratory Abnormalities (Laboratory Abnormalities/Person-Years) † Blood phenylalanine concentration below 30 micromol/L LLN – lower limit of normal ULN – upper limit of normal Hs – high sensitivity

 

Description Of Selected Adverse Reactions

Arthralgia

In clinical trials, 245 out of 285 (86%) patients experienced episodes consistent with arthralgia (includes back pain, musculoskeletal pain, pain in extremity, and neck pain).

Arthralgia episodes were more frequent during the induction/titration phase (7.4 episodes/patient-year) and decreased over time (1.4 episodes/patient-year in the maintenance phase).

Forty-four out of 285 (15%) patients had one episode of arthralgia, 32 (11%) patients had 2 episodes of arthralgia, 18 (6%) had 3 episodes of arthralgia, and 146 (51%) had 4 or more episodes of arthralgia. Arthralgia occurred as early as after the first dose of Palynziq and occurred at any time during treatment. The mean duration of arthralgia was 16 days (median: 3 days, range: 1 to 936 days), and 19% of arthralgia episodes had a duration of at least 14 days. Severe arthralgia (severe pain limiting self-care activities of daily living) was reported by 11 (4%) patients. In addition to arthralgia, other joint-related signs and symptoms reported were: joint swelling (24 patients; 8%), joint stiffness (22 patients; 8%), and musculoskeletal stiffness (20 patients; 7%). Arthralgia episodes were managed with medications (e.g., nonsteroidal anti-inflammatory drugs, glucocorticoids, and acetaminophen), Palynziq dosage reduction (4% of episodes), Palynziq interruption (4% of episodes), or Palynziq withdrawal (0.6% of episodes). 97% of arthralgia episodes were reported as resolved at the time of last observation (up to 77 months of follow-up).

Injection Site Reactions

Injection site reactions were reported as early as after the first dose of Palynziq and occurred at any time during treatment. Injection site reactions were more frequent during the induction/titration phase  (21 episodes/patient-years) and decreased over time (3 episodes/patient-years in the maintenance phase). The mean duration of injection site reaction was 10 days (median: 2 days, range: 1 to 1612 days), and 8% of injection site reactions had a duration of at least 14 days. 99% of injection site reactions were reported as resolved at the time of last observation (up to 77 months of follow-up).

Three injection site reactions consistent with granulomatous skin lesions were reported (each reaction occurring in one patient): granulomatous dermatitis (occurred after 464 days of Palynziq treatment and lasted 16 days), xanthogranuloma (occurred after 378 days of Palynziq treatment and lasted 638 days) was treated with a topical antihistamine, corticosteroid, and Palynziq treatment was discontinued, and necrobiosis lipoidica diabeticorum (occurred after 281 days of Palynziq treatment and lasted 281 days). Necrobiosis lipoidica diabeticorum was treated with steroid injections and complicated by Pseudomonas infection. All three injection site reactions resolved.

One patient reported soft tissue infection (occurred after 196 days of Palynziq treatment and lasted 8 days) associated with mesenteric panniculitis treated with antibiotics, which resulted in treatment discontinuation.

Generalized Skin Reactions (not limited to the injection site) Lasting At Least 14 Days

In clinical trials, 134 out of 285 (47%) patients treated with Palynziq experienced generalized skin reactions (not limited to the injection site) lasting at least 14 days. Mean duration of these reactions was 63 days (median: 37 days; range: 14 to 638 days). Generalized skin reactions were more frequent during the induction/titration phase (0.7 episodes/patient-years), and decreased over time (0.3 episodes/patientyears in the maintenance phase).

The mean time from first dose of Palynziq to onset of skin reactions was 373 days (median: 213 days; range: 2 to 1970 days). 5% of these reactions persisted at least 180 days, and 86% of these reactions were reported as resolved at the time of last observation (up to 77 months of follow-up).

Angioedema

In clinical trials, 22 out of 285 (8%) patients experienced 45 episodes of angioedema (symptoms included: pharyngeal edema, swollen tongue, lip swelling, mouth swelling, eyelid edema and face edema) occurring independent of anaphylaxis. Angioedema (included under Hypersensitivity in Table 2) was more frequent during the induction/titration phase (0.14 episodes/patient-year) and decreased over time (0.04 episodes/patient-year in the maintenance phase). Three patients discontinued treatment. All episodes resolved. Angioedema can present as a symptom of anaphylaxis.

Serum Sickness

In clinical trials, serum sickness was reported in 7 out of 285 (2%) patients. Serum sickness episodes were more frequent during the induction/titration phase (0.04 episodes/patient-year) and decreased over time (less than 0.01 episodes/patient-year during the maintenance phase). All serum sickness reactions resolved without sequelae (duration of serum sickness ranged from 1 to 8 days). Out of the 7 patients who experienced serum sickness, 5 patients continued treatment without a recurrence, and managed serum sickness with drug interruption, dosage reduction and/or concomitant medication. Two patients discontinued treatment.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Palynziq in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

All patients treated with Palynziq developed a sustained total anti-drug antibody (TAb) response with a majority of patients (91%; N = 235/258) developing that response by Week 4 of treatment. Mean TAb titers peaked 2 weeks after Palynziq initiation and remained elevated throughout treatment (greater than 3 years after treatment initiation). Anti-phenylalanine ammonia lyase (PAL) IgM antibodies were detected in a majority of patients (98%; N = 265/270) by 2 months after treatment initiation, with incidence declining over time to 67% at 36 months (N = 114/171). Anti-PAL IgG antibodies were detected in almost all patients (N = 226/227) by 4 months after treatment initiation. Mean anti-PAL IgM and IgG titers peaked at approximately 3 and 6 months, respectively, after treatment initiation and remained elevated throughout treatment (greater than 3 years after treatment initiation). Drug-induced anti-PEG IgM and IgG antibodies were detected in the majority of patients (98%; N = 277/284 for IgM; and 278/284 for IgG) with mean titers for both peaking at 1 to 3 months after treatment initiation. Neutralizing antibodies (NAb) capable of inhibiting PAL enzyme activity were detected on at least one measurement in the majority of patients (89%; N = 253/284) over time. Mean NAb titers peaked and reached a plateau at 16 to 20 weeks of treatment and then remained present throughout treatment (greater than 3 years after treatment initiation).

Twenty-seven of 29 patients who had anaphylaxis were tested for anti-pegvaliase-pqpz IgE antibodies, which recognize the PEGylated protein product. Of the 27 patients tested for anti-pegvaliase-pqpz IgE antibodies, 26 patients tested negative. The one patient who tested positive for anti-pegvaliase-pqpz IgE antibodies on the screening test did not have sufficient sample to confirm IgE positivity. This patient tested negative for anti-pegvaliase-pqpz IgE at routine visits prior to and after the anaphylaxis episode (not at times of anaphylaxis). Sixty-seven of 285 patients in clinical trials were tested for both anti-PAL IgE antibodies, which recognize the recombinant PAL protein, and for anti-pegvaliase-pqpz IgE antibodies during routine study visits (not at times of anaphylaxis episodes) or during additional visits for hypersensitivity reactions. Of those 67 patients, 5 (8%) tested positive at least once for anti-PAL IgE antibodies but negative for anti-pegvaliase-pqpz IgE antibodies.

The highest frequency of hypersensitivity reactions (consistent with a Type III immune complex-mediated hypersensitivity mechanism) occurred within the first 6 months of Palynziq treatment when the mean circulating immune complex (CIC) concentrations were at their highest and mean complement C3 and C4 concentrations were at their lowest. Mean CIC concentrations decreased and complement levels increased over time as the exposure-adjusted rate of hypersensitivity reactions decreased. IgG and IgM CIC concentrations were above the upper limit of normal in 63% (N = 164/259) and 42% of patients (N = 109/259), respectively, at 12 weeks of Palynziq treatment and returned towards baseline with long-term treatment (greater than 3 years after treatment initiation). 61% of patients (N = 110/180) had complement C3 concentrations less than lower limit of normal (LLN) at 6 months after treatment initiation and 38% of patients (N = 94/248) had complement C4 concentrations less than LLN at 3 months after treatment initiation. The incidence of low complement C3 and C4 concentrations decreased over time, but approximately 35% (N = 34/96) and 12% (N = 11/96) of patients had low C3 and C4 concentrations, respectively, at 36 months after treatment initiation.

Higher antibody responses for all antibody analytes, including NAb, were associated with lower mean trough pegvaliase-pqpz concentrations and with higher blood phenylalanine concentrations. Hypersensitivity reactions occurred more frequently in patients with higher antibody titers for some but not all antibody analytes. Patients with higher mean change in IgG CIC concentrations from pre-treatment baseline tended to have higher discontinuation rates than patients with lower mean change in IgG CIC concentrations. Mean antibody titers for anti-PAL IgG and IgM, TAb, and NAb remained relatively stable with long-term treatment.