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Bloomberg CFF and Vertex Funding Details

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great article on cost of Orkambi

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Monitoring Parameters     CF mutation test (prior to therapy if genotype is unknown); blood pressure periodically (during therapy); ophthalmological examinations (baseline and follow-up in pediatric patients); ALT, AST, and bilirubin (baseline, every 3 months for the first year of therapy, and annually thereafter; increased monitoring may be necessary in patients with a history of elevated hepatic transaminases or bilirubin); signs and symptoms of respiratory effects (in patients with a percent predicted FEV1 <40)

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Monitoring Parameters     CF mutation test (prior to therapy if genotype is unknown); blood pressure periodically (during therapy); ophthalmological examinations (baseline and follow-up in pediatric patients); ALT, AST, and bilirubin (baseline, every 3 months for the first year of therapy, and annually thereafter; increased monitoring may be necessary in patients with a history of elevated hepatic transaminases or bilirubin); signs and symptoms of respiratory effects (in patients with a percent predicted FEV1 <40)

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CYP3A metabolism - need to adjust dosage of other meds.

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CYP3A metabolism - need to adjust dosage of other meds.

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Menstrual irregularities were more frequent in women taking lumacaftor-ivacaftor

Adverse Reactions Significant>10%:Cardiovascular: Chest discomfort (≤22%)Gastrointestinal: Nausea (13%), diarrhea (12%)Respiratory: Dyspnea (13% to ≤22%), changes in respiration (9% to ≤22%), nasopharyngitis (13%)1% to 10%:Cardiovascular: Increased systolic blood pressure (>140 mmHg: ≤4%), increased diastolic blood pressure (>90 mmHg: ≤2%)Central nervous system: Fatigue (9%)Dermatologic: Skin rash (7%)Endocrine & metabolic: Menstrual disease (10%; including amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular; more common in patients using hormonal contraceptives)Gastrointestinal: Flatulence (7%)Infection: Influenza (5%)Neuromuscular & skeletal: Increased creatine phosphokinase (≤7%)Respiratory: Upper respiratory tract infection (10%), rhinorrhea (6%)<1% (Limited to important or life-threatening): Hepatic encephalopathy, increased serum bilirubin, increased serum transaminases

ContraindicationsThere are no contraindications listed in the US labeling.

Concerns related to adverse effects:

• Cataracts: Noncongenital lens opacities and cataracts have been reported in pediatric patients treated with ivacaftor; other risk factors were present in some cases (eg, corticosteroid use, exposure to radiation), but a possible risk related to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients.

• Hepatic effects: May increase hepatic transaminases with or without concomitant elevations in total serum bilirubin. Monitor ALT, AST, and bilirubin at baseline, every 3 months for the first year of therapy, and annually thereafter. Increased monitoring may be necessary in patients with a history of elevated hepatic transaminases or bilirubin. Temporarily discontinue treatment if ALT or AST >5 times ULN without concomitant elevated bilirubin or if ALT or AST >3 times ULN with concomitant bilirubin >2 times ULN.

• Hypertension: Increased blood pressure has been observed; monitor blood pressure periodically during therapy.

• Respiratory effects: Use was associated with an increased incidence of respiratory events (eg, chest discomfort, dyspnea, and abnormal respirations). Careful monitoring during initiation of therapy is recommended in patients with a percent predicted FEV1 <40.

Disease-related concerns:

• Hepatic impairment: Use with caution; worsening of liver function (including hepatic encephalopathy) has been reported in patients with advanced liver disease. Dosage adjustment is recommended in patients with moderate to severe (Child-Pugh class B or C) impairment.

• Renal impairment: Use with caution in patients with severe impairment (CrCl ≤30 mL/minute) or end-stage renal disease (ESRD).

Special populations:

• Organ transplant recipients: Use is not recommended in cystic fibrosis patients who have undergone organ transplantation (has not been studied).

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- Significant improvements in percentage of predicted FEV1 in all groups, seen by day 15 and sustained
- Significant reductions in the rate of pulmonary exacerbations--> less hospitalization and IV antibiotic treatment
- Both FEV1 and rate of exacerbation are good predictors of survival
- TRANSPORT study improved patient BMI (but not TRAFFIC)
- This specific mutation accounts for 45% of patients with CF, so is a huge milestone treatment that can help many people
- Acceptable side effect profile
- Improvement according to CFQ-R (patient assessed function)

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4 special designations
1. fast track - serious conditions w/ "unmet medical need'
2. breakthrough therapy - substantial improvement over existing therapy; it's a preliminary approval w/ lower evidence threshold than standard approval
3. accelerated approval - for serious/life-threatening disease; need only show benefit in surrogate endpoint
4 . priority review - treats a serious condition and would be significant improvement in safety or effectiveness; FDA will take action on application w/in 6 months

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-Basically, 2 tablets taken every 12 hours.  (4 tablets daily) with fat containing food
-Reduce dose with hepatic impairement
-Reduce dose with CYP3A inhibitors
-Efficacy and effects in patients <6 years not established

http://pi.vrtx.com/files/uspi_lumacaftor_ivacaftor.pdf

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In two 24-week trials in the approved patient population (TRAFFIC and TRANSPORT), lumacaftor 400 mg plus ivacaftor 250 mg, administered every 12 h in combination with standard therapy, was associated with an ≈3 % statistically significant improvement in lung function relative to placebo (as measured by the percent predicted forced expiratory volume in 1 s). Lumacaftor plus ivacaftor did not significantly improve respiratory symptoms, although reduced pulmonary exacerbations to a clinically meaningful extent and, in one trial (TRANSPORT), significantly improved body mass index (BMI).

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http://tar.sagepub.com.ezproxy.uvm.edu/content/9/6/313.long

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Contraceptives (Estrogens): Lumacaftor may decrease the serum concentration of Contraceptives (Estrogens). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required. Risk D: Consider therapy modification

Contraceptives (Progestins): Lumacaftor may decrease the serum concentration of Contraceptives (Progestins). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required. Risk D: Consider therapy modification

Significant - Monitor Closely

lumacaftor/ivacaftor + omeprazole

lumacaftor/ivacaftor will decrease the level or effect of omeprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lumacaftor/ivacaftor is a strong CYP3A4 inhibitor and also has the potential to induce CYP2C19 and both induce and inhibitor P-gp.

lumacaftor/ivacaftor, omeprazole. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. .

tobramycin inhaled + azithromycin

tobramycin inhaled and azithromycin both increase nephrotoxicity and/or ototoxicity. Modify Therapy/Monitor Closely. Avoid concurrent or sequential use to decrease risk for ototoxicity

Food Interactions Food increases exposure to lumacaftor and ivacaftor. Ivacaftor serum concentrations may be increased when taken with grapefruit or Seville oranges (Kalydeco prescribing information, 2015). Management: Administer with fat-containing food; avoid grapefruit and Seville oranges during therapy.

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Most significant Adverse reactions (from up to date)

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Most significant Adverse reactions (from up to date)

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- chest discomfort
- Nausea
- Diarrhea
- dyspnea and changes in respiration
- Nasopharyngits

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Discussion of insurance companies deciding whether or not to cover Orkambi

-possible consideration for requiring certain severity of disease in order for this to be covered
-concern over the high cost relative to modest increase in lung function
-restrict access to coverage

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https://www.cff.org/Living-with-CF/Treatments-and-Therapies/Inhaled-Medications/CFTR-Modulator-Therapies/

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https://www-uptodate-com.ezp.med.uvm.edu/contents/lumacaftor-and-ivacaftor-drug-information?source=search_result&search=Orkambi&selectedTitle=1~6

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Phase 3 trial for Orkambi

Increased FEV1
decreased pulmonary exacerbations
decreased hospitalization
improved BMI

Side effects:
dyspnea
chest tightness
elevated liver enzymes with serious