Reading the pharmacology of a newly approved drug
A newly approved drug is described by what it acts on and how the body handles it, what it interacts with and what harm it does, how it is dosed, where it stands among existing treatments and what it costs, how large its measured effect is, and what conditions a regulator attaches when the evidence behind it is thin.
Antihypertensives
Aliskiren was approved by the FDA in March 2007 for hypertension, as a single agent or in combination with other drugs. In clinical trials it had been used with other antihypertensive drugs to improve blood pressure control. Its mechanism of action differs from those of the other antihypertensive drugs then available: it inhibits renin and the activation of the renin-angiotensin-aldosterone system, whereas the angiotensin-converting-enzyme (ACE) inhibitors, the "pril" antihypertensives, and the angiotensin II receptor blockers such as losartan affect only angiotensin. In theory, blocking the renin pathway may help prevent end-organ damage in hypertension, but long-term trials had not been performed. High-fat meals significantly reduce its absorption. It has a half-life of about 24 hours and takes 7 to 8 days to reach steady state. It is partially metabolised in the liver by cytochrome P450 3A4, and it can interact with drugs that affect that enzyme. Like the ACE inhibitors it can cause cough, though at a lower rate, and like both the ACE inhibitors and the receptor blockers it is contraindicated in pregnancy. Treatment cost $60 to $90 a month.
Nebivolol was approved by the FDA in December 2007 for hypertension, alone or in combination with other antihypertensive agents, and it has also been used off-label for heart failure. It is a beta-blocker, more specifically a third-generation beta-adrenergic antagonist with high beta-1 cardiac selectivity, and it acts by peripheral vasodilation, through increased production and release of nitric oxide together with decreased nitric oxide degradation. Clinical studies had found it similar to other available drugs at reducing blood pressure, with several potential advantages over other beta-blockers: it may reduce cardiac contractility less, and its high cardioselectivity may make it safer in patients with asthma, although that had not been proven clinically. Preliminary research suggested that it may be more effective than other beta-blockers in black individuals, a finding that had to be confirmed in further trials. It may be inferior to other beta-blockers when used for heart failure in the elderly. It is metabolised by cytochrome P450 2D6, has a half-life of 12 hours and active metabolites that also block beta receptors, and reaches peak concentration in about 1.5 to 4 hours. Like other beta-blockers it must be discontinued gradually over one to two weeks, because abrupt discontinuation can lead to severe exacerbation of angina, myocardial infarction or arrhythmias. Treatment cost about $60 a month.
Clevidipine is an injectable calcium channel blocker, approved by the FDA in August 2008. It has a half-life of less than one minute and is 99.5% protein bound, and its advantages include quick onset of antihypertensive effect and ease of use, since the dose is not weight-based. It decreases the influx of calcium during depolarisation in arterial smooth muscle and reduces mean arterial blood pressure by decreasing systemic vascular resistance. In clinical trials of hypertensive emergency it controlled blood pressure in most patients within 30 minutes and was not associated with hypotension. It is given as an intravenous infusion titrated to goal blood pressure, and the infusion is stopped once pressure is adequately controlled, when oral antihypertensive treatment can start. It is supplied in a lipid emulsion vehicle; it cannot be used in patients with allergy to soy or egg products. It cost approximately $360 for a 100 mL vial, which provides blood pressure control for about ten minutes.
Carbapenem antibiotics
Doripenem is an injectable broad-spectrum carbapenem, approved by the FDA in October 2007 for complicated urinary tract infection, including pyelonephritis, and for complicated intra-abdominal infections. Its manufacturer was also seeking approval for hospital-acquired pneumonia. It binds penicillin-binding proteins and inhibits cell wall synthesis. It has broad bactericidal activity against gram-positive, gram-negative and aerobic bacteria, activity against Candida fungi and increased activity against Pseudomonas aeruginosa, but like other carbapenems it is not effective for Enterococcus faecium or methicillin-resistant Staphylococcus aureus. One advantage is that it might be less likely than other carbapenems to cause seizures. Treatment cost about $138 a day.
By 21 September 2018 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had recommended meropenem with vaborbactam (Vabomere) for EU marketing authorisation. It is a fixed combination of vaborbactam, a new beta-lactamase inhibitor, with meropenem, a broad-spectrum carbapenem already approved in the EU, and it is given by infusion into a vein. By 2018 the lack of medicines to treat patients with infections caused by resistant bacteria had become a major problem. Beta-lactamases are enzymes involved in bacterial resistance to carbapenems. By inhibiting them, vaborbactam protects meropenem from being inactivated and restores its activity against many, but not all, carbapenem-resistant pathogens. The indications recommended, in adults, were complicated urinary tract infection including pyelonephritis, a sudden and severe infection that causes the kidneys to swell and may permanently damage them; complicated intra-abdominal infection; hospital-acquired pneumonia including ventilator-associated pneumonia; bacteraemia associated with any of those; and infections due to aerobic Gram-negative organisms in adults with limited treatment options. In the clinical development programme, exposure to vaborbactam at the recommended dose was shown to be sufficient to protect meropenem's activity against carbapenem-resistant Enterobacteriaceae. The CHMP agreed that the studies did not indicate any major concerns about the combination's safety profile.
Antibodies for migraine prevention
Erenumab and galcanezumab, two monoclonal antibodies recommended in 2018 for EU marketing authorisation for the prevention of migraine, belong to a new class of medicines that block the activity of calcitonin gene-related peptide, a molecule involved in migraine attacks. Migraine is estimated to affect approximately 15% of the European population. It is likewise estimated to affect approximately 15% of the population of the EU. Patients have recurrent episodes of intense, throbbing headache, most often on one side of the head, sometimes preceded by visual or sensory disturbances known as an aura, and many also have nausea, vomiting and increased sensitivity to light or sound. Migraine can substantially impair a patient's ability to function physically, at work or school, and socially. Its exact cause is unknown, but it is believed to be a neurovascular disorder with disease mechanisms both within the brain and in the blood vessels of the head. It is most frequent in women and has a strong genetic component. There is no cure, but treatments are available both to tackle the symptoms and to reduce the frequency of migraine days. Existing preventive treatments are frequently associated with variable efficacy and poor safety and tolerability, so there was an unmet medical need for new treatment options. Existing preventive treatments also do not always work well and may have unpleasant side effects.
Erenumab (Aimovig), recommended in May 2018, was the first human monoclonal antibody therapy for migraine prevention to be recommended for marketing authorisation. It was studied in two pivotal trials that enrolled 667 patients with chronic and 955 with episodic migraine. After three months the chronic group averaged 2.5 fewer monthly migraine days than placebo, while the episodic group had either 1.3 or 1.8 fewer depending on dose, and the most common adverse events were injection site reactions, constipation, muscle spasms and pruritus. It should only be taken by patients with at least four migraine days a month, as a solution for injection given once a month that patients can inject themselves after appropriate training.
Galcanezumab (Emgality), recommended by 21 September 2018, was the second monoclonal antibody therapy for migraine prevention to be recommended for authorisation, after the positive opinion for erenumab in May 2018. It was studied in three pivotal trials involving 1,780 patients with episodic migraine and 1,117 with chronic migraine. After six months of treatment, patients with episodic migraine had on average 1.9 fewer monthly migraine days than with placebo, and patients with chronic migraine 2 fewer; the most common side effects were pain and reactions at the injection site, vertigo and constipation. It is a solution for injection intended only for patients with at least four migraine days a month. The two medicines widen the therapeutic options for migraine.
Medicines for rare diseases
Sapropterin dihydrochloride, an orphan drug approved by the FDA in December 2007, slows the effects of phenylketonuria, a genetic disorder in which the phenylalanine hydroxylase enzyme that helps break down phenylalanine is missing or does not function properly. It is a synthetic form of tetrahydrobiopterin, which has produced a response in 20% to 56% of individuals with the condition. In clinical trials the phenylalanine level dropped by 30% in approximately half of patients. Reductions in phenylalanine are seen within 24 hours, and the maximum effect occurs in one month. It must be combined with a phenylalanine-restricted diet that avoids the phenylalanine in proteins such as meat, dairy and eggs. It cost about $250 a day, and the manufacturer had set up a programme to help patients and families work with third-party payers and the National Organization for Rare Disorders.
Inotersen (Tegsedi) had been recommended for EU marketing authorisation by 1 June 2018 for stage 1 or stage 2 polyneuropathy in hereditary transthyretin amyloidosis, a rare disease estimated to be diagnosed in approximately three cases per ten million people in Europe each year. In the disease the blood protein transthyretin is defective and breaks easily, and the broken protein forms amyloid that builds up in the peripheral nervous system and in organs such as the gastrointestinal tract, kidney and heart, where it interferes with their normal functions. Inotersen is an antisense oligonucleotide, a very short piece of synthetic DNA designed to attach to the genetic material of the cells responsible for producing transthyretin. It is expected to decrease transthyretin production, thereby reducing the formation of amyloid and relieving the symptoms. It was designated an orphan medicine in 2014 and evaluated in patients with stage 1 or stage 2 but not stage 3 polyneuropathy, where it showed clinically relevant effects on the neurological manifestations of the disease and on quality of life. The existing options, liver transplant, tafamidis and off-label use of a non-steroidal anti-inflammatory drug, all have considerable limitations for patients with stage 2 and stage 3 polyneuropathy, so there was a clear unmet medical need, and the CHMP therefore considered inotersen of major interest for public health and agreed to the applicant's request for accelerated assessment.
Voretigene neparvovec (Luxturna), a gene therapy, had been recommended by 21 September 2018 for adults and children with inherited retinal dystrophy caused by RPE65 gene mutations, a rare genetic disorder that causes vision loss and usually leads to blindness. The RPE65 gene encodes one of the enzymes involved in the biochemistry of light capture by retinal cells, and its mutations hinder the ability to detect light. The disease is severely debilitating, with progressive loss of vision, and most patients will be blind by young adulthood; there was no treatment, and support was limited to measures such as low-vision aids. Voretigene neparvovec delivers a functional RPE65 gene into retinal cells through a single retinal injection, restoring the production pathway for the enzyme there and thereby improving the patient's ability to detect light. It is meant for patients with confirmed biallelic mutations, inherited from both parents, who have sufficient viable retinal cells, and it was the first gene therapy recommended for approval for a retinal disease. It was studied in 41 patients. In the main trial, treated patients showed a significant improvement of night vision, one of the typical symptoms of the disease, after one year while the control group showed none, and the most common side effects were conjunctival hyperaemia, cataracts and increased intraocular pressure. Given the novelty of the treatment and the limited number of treated patients, the CHMP required the company to ensure long-term follow-up of patients to confirm continuing efficacy and safety. The follow-up studies agreed included a post-authorisation safety study based on a disease registry of patients with vision loss due to the condition, and a 15-year follow-up programme of efficacy and safety outcomes for all patients treated in the clinical programme. The CHMP's opinion was based on the assessment by the EMA's Committee for Advanced Therapies, and the product was designated an orphan medicine and an advanced therapy medicinal product, with the EMA providing protocol assistance during its development.
Satralizumab (Enspryng), recommended for EU marketing authorisation by 23 April 2021, is for neuromyelitis optica spectrum disorders (NMOSD) in adults and adolescents from 12 years of age who are positive for anti-aquaporin-4 antibodies. NMOSD is a rare and life-threatening condition, estimated to affect approximately 1 to 2 in 100,000 people in the EU, that most commonly affects the optic nerves and spinal cord and can lead to reduction or loss of vision, loss of sensation, loss of bowel and bladder control, weakness and paralysis of the arms and legs. It is thought to be caused by an abnormal reaction of the immune system that damages healthy nerve cells, and it is characterised by relapsing attacks, with symptoms coming back periodically. Satralizumab is an antibody designed to block the inflammatory effects of the interleukin-6 receptor, which is involved in the pathogenesis of NMOSD, and it works by reducing and preventing the attacks. It is given by injection under the skin from a pre-filled syringe, with the first three injections 2 weeks apart followed by one every 4 weeks, on its own or with immunosuppressive therapy. The opinion rested mainly on two randomised studies in 184 patients. In the 119 anti-aquaporin-4-positive patients, the chance of a relapse with satralizumab, alone or with immunosuppressive therapy, was a quarter of that in the control group receiving placebo alone or with immunosuppressive therapy. The most common side effects in the trials were headache, joint pain, decreased white blood cell count and reactions at the injection site.
Elivaldogene autotemcel (Skysona), a gene therapy recommended by 21 May 2021, is for children with cerebral adrenoleukodystrophy (CALD), a severe form of a rare inherited neurological disease that is seen almost exclusively in males, affects the brain and leads to an irreversible loss of neurological functions. CALD is the most common form of adrenoleukodystrophy, a rare disease affecting approximately 1 in 21,000 newborn males and caused by abnormalities in the ABCD1 gene, which is responsible for producing the adrenoleukodystrophy protein. Without the protein, patients cannot break down very long chain fatty acids, which build up in brain cells and lead to inflammation and destruction of the myelin sheath that insulates the nerves and improves the way they function. Forty percent of boys diagnosed with adrenoleukodystrophy develop CALD, typically during childhood, and if untreated nearly half of patients with CALD die within 5 years of symptom onset. No medicine was approved for it, and the only intervention available was transplantation of stem cells from a donor. Transplantation presents several potential complications and risks, which are reduced for patients with a matching sibling donor, but such patients are fewer than 30% of patients with CALD, so there was an unmet medical need. The product was designated an orphan medicinal product on 6 June 2012 and is indicated for early cerebral adrenoleukodystrophy in patients under 18 years of age with an ABCD1 mutation for whom a human leukocyte antigen-matched sibling haematopoietic stem cell donor is not available. The therapy is made of immature bone marrow cells taken from the patient and modified by a lentivirus, changed so as not to cause disease in humans, that carries a functional copy of the ABCD1 gene into them. Given back by infusion into a vein, the cells are expected to spread through the body and develop into healthy cells, including brain cells, that produce the missing protein, so that patients should be able to break down the accumulated fatty acids, which will help to reduce symptoms. It is a one-time treatment that can only be given in a specialised hospital by doctors experienced in treating CALD, transplanting bone marrow and using gene therapy medicines. The recommendation rested on a single-arm trial that enrolled 32 male patients aged 17 or younger, whose results were compared with those of a study in which 59 patients had a stem cell transplant from a matched sibling or matched non-sibling donor. All patients in the main trial were enrolled in a long-term follow-up study. An analysis of 30 enrolled patients 24 months after infusion concluded that for 27 of them (90%) the treatment preserved motor function and communication ability and improved survival compared with untreated patients at an early stage of cerebral disease. The most serious adverse reaction in the trials was pancytopenia. Adding a new gene into stem cells could theoretically cause blood cancers, which was not seen during the trial, but after treatment patients are monitored with blood tests for any signs of blood cancer. Further long-term efficacy and safety data are being collected through an ongoing study and a long-term registry, and all results must be included in post-marketing safety reports, which the EMA continuously reviews.
Odevixibat (Bylvay), recommended by 21 May 2021, is for progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older. PFIC is a rare, life-threatening liver disease in which liver cells are less able to secrete bile, and the build-up of bile in them causes liver disease. Symptoms typically develop in infancy, usually in the first months of life, and only about half of affected children survive beyond the age of 10 years. Severe itching is common in children with PFIC and can lead to sometimes serious scratching injuries, loss of sleep, irritability and poor attention, and if untreated many patients progress to end-stage liver disease and require liver transplantation. The unmet need was high, and treatment options were limited to surgical intervention and off-label symptomatic medical therapies. Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter that acts locally in the distal ileum, reducing the reuptake of bile acids and increasing their clearance through the colon. It was designated an orphan medicinal product on 17 July 2012, accepted into the EMA's PRIME scheme on 13 October 2017, and reviewed under the CHMP's accelerated assessment procedure. The main study was a double-blind, randomised, placebo-controlled phase 3 study in children with PFIC. It showed a significant reduction in serum bile acids accompanied by a significant reduction in pruritus, maintained in an ongoing long-term open-label follow-up study, with hepatic parameters and fibrosis scores improving or stable for the duration of the study, at most 72 weeks. The most common side effects were diarrhoea, abdominal pain, haemorrhagic diarrhoea, soft faeces and hepatomegaly, and no clinically significant differences in the pharmacokinetic, safety and tolerability profile were observed by age, sex or race. Because PFIC is very rare, the CHMP agreed that it is not possible to provide comprehensive data on efficacy under normal conditions of use, so it recommended a marketing authorisation under exceptional circumstances. More data were needed to determine whether odevixibat can delay disease progression and the need for liver transplantation, so the CHMP requested a registry-based study to further characterise its efficacy in patients aged 6 years or older.
Combination products
Combination products newly marketed in 2007 and 2008 included amlodipine with olmesartan (Azor) and amlodipine with valsartan (Exforge) for hypertension, brimonidine with timolol (Combigan) for glaucoma, and sitagliptin with metformin (Janumet) for diabetes.