Ravulizumab

38194311000001107

New Medicines

UltomirisParoxysmal nocturnal haemoglobinuria (PNH) in adults - first-line

Information

Ultomiris
New molecular entity
Alexion
Alexion

Development and Regulatory status

Launched
Approved (Licensed)
Launched
March 2021
Yes
Mar 21Available in UK. 100mg/ml conc for soln for inf in vial, 3ml=£4,533.00; 11ml=£16,621.00 [17].
Sep 19Ravulizumab was withdrawn from the Community Register of designated orphan medicinal products on 11 June 2019 on request of the sponsor [16].
Jul 19Alexion is awaiting a positive recommendation from NICE and agreed funding from NHS England before providing a price or launch date. They are working with the HTA body to ensure a timely appraisal [15].
Jul 19Alexion announced that the European Commission has approved ravulizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) as below ref 12 [13].
Apr 19CHMP has adopted a positive opinion for ravulizumab for the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) with haemolysis with clinical symptoms indicative of high disease activity and those treated with eculizumab for 6 months who are clinically stable [12].
Mar 19A new market research report identifies ravulizumab as one of seven new drugs it believes will hit sales of $1 billion or more, the so-called “blockbuster” mark, by 2023 [11].
Feb 19One month after launch of Ultomiris, Alexion announce 5% of US patients have switched from Soliris (eculizumab) and virtually 100% of new starts are with Ultomiris. The company aims for a 70% switch in 2 years and has similar ambitions for Europe, starting with Germany, where launch is anticipated mid 2019 [10].
Dec 18FDA has approved ravulizumab (ULTOMIRIS™) for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) [9].
Jun 18Filed in EU for treatment of patients with PNH. The application is supported by comprehensive data from two PIII trials in more than 440 patients (the largest population of patients with PNH ever studied in Phase 3), which included patients who had never received a complement inhibitor, and patients who were stable on Soliris® (eculizumab) and switched to ALXN1210 [8].
Mar 18The company announched plans for regulatory submissions of ALXN1210 in PNH in the US., EU and Japan in the 2nd half of 2018 [6].
Jul 17Will be filed in the EU via the centralised procedure [5].
Jan 17ALXN 1210 gains orphan drug status for paroxysmal nocturnal haemoglobinuris in the US; orphan designation in the EU was granted in June 2016. A PIII trial in the US has recently started and a PII trial (NCT02605993, EudraCT2015-002674-20) is in progress in several countries including the UK [1].

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor
PNH is a very rare acquired bone marrow disorder characterised by intravascular haemolysis, with resultant anaemia; before effective treatments were available, median survival was 10 years from diagnosis and half of those affected died from complications. Spontaneous recovery may occur, but only in a minority of patients. [2] UK incidence is about 0.13/100,000/year and 15-year prevalence is likely to be around 1.59/100,000 [3].
Paroxysmal nocturnal haemoglobinuria (PNH) in adults - first-line
Intravenous

Further information

Yes
To be confirmed

Trial or other data

Apr 18Positive topline data from ALXN1210 PIII switch study. The study showed pts with PNH can be effectively and safely switched from Soliris® (eculizumab) every 2 weeks to ALXN1210 every 8 weeks. The study demonstrated non-inferiority of ALXN1210 vs. Soliris® in pts with PNH who were stable on Soliris® based on change in LDH levels. The study also demonstrated non-inferiority on four key secondary endpoints: the proportion of pts with breakthrough hemolysis, change from baseline in quality of life, the proportion of pts avoiding transfusion and the proportion of pts with stabilised Hb levels. No pts treated with ALXN1210 experienced breakthrough haemolysis vs. 5 pts treated with Soliris®. ALXN1210 was well tolerated with a safety profile consistent with that of Soliris®. No pt withdrew from the study due to adverse events and no anti-drug antibody was observed for ALXN1210; one was observed for Soliris®. There were no cases of meningococcal infection observed in either the ALXN1210 or Soliris® arms.[7]
Mar 18Postive topline data from PIII trial comparing ALXN 1210 to eculizumab in treatment-naïve PNH pts. The co-primary endpoints were avoidance of transfusions and normalisation of lactate dehydrogenase (LDH) levels (a direct marker of complemented-mediated hemolysis). ALXN1210 showed non-inferiority for all four key secondary endpoints.The safety profiles of the two drugs were reported to be basically the same [6].
Oct 16PIII trial is in progress (NCT02946463), currently in the US only: it is an open label randomised comparison of ALXN1201 every 8 weeks with eculizumab every 2 weeks; primary outcomes are normalisation of lactate dehydrogenase levels and transfusion avoidance, both over 26 weeks, estimated recruitment will be 214, and estimated primary completion Dec 2017 [4].

Evidence based evaluations

UltomirisAtypical haemolytic uraemic syndrome in adults and children ≥10kg

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

Launched
Approved (Licensed)
Launched
March 2021
Yes
Yes
Mar 21Available in UK. 100mg/ml conc for soln for inf in vial, 3ml=£4,533.00; 11ml=£16,621.00 [10].
Jun 20Approved in EU for treatment of adults and children with a body weight of 10 kg or above with aHUS who are complement inhibitor treatment-naïve or have received eculizumab for at least three months and have evidence of response to eculizumab [9].
Apr 20Recommended for EU approval by CHMP - the additional indication is "in the treatment of patients with a body weight of 10 kg or above with atypical haemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received eculizumab for at least 3 months and have evidence of response to eculizumab" [8].
Oct 19FDA approved including for treatmend of patients one month of age and older [7].
Jul 19Also pre-registration in EU [6].
Jun 19Filed in the US where it has been granted priority review status. Target action date set at 19 October 2019 [5].
May 18Will be filed in EU using centralised procedure [3].

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor
Atypical hemolytic-uremic syndrome (aHUS) is a thrombotic microangiopathy characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction. Prevalence is 1-9 per 1,000,000 people [1].
Atypical haemolytic uraemic syndrome in adults and children ≥10kg
Intravenous

Further information

Yes
To be confirmed

Trial or other data

Jan 19PIII ULTOMIRIS aHUS-311 study (NCT02949128)meets primary endpoint. This global, multicentre, single arm study evaluated the safety and efficacy of i.v. ULTOMIRIS administered in 56 adults (≥ 18) who hadn’t been treated with a complement inhibitor before. Pts received a weight-based loading dose (≥ 40 to < 60 kg = 2,400 mg; ≥ 60 to < 100 kg = 2,700 mg; ≥ 100 kg = 3,000 mg) on day 1, followed by weight-based maintenance doses (≥ 40 to < 60 kg = 3,000 mg; ≥ 60 to < 100 kg = 3,300 mg; ≥ 100 kg = 3,600 mg) on day 15 and then once every 8 weeks. Complete TMA response (= primary endpoint, defined as normalisation of platelet count AND lactate dehydrogenase (LDH) level AND an improvement in serum creatinine of ≥ 25%) over 26-weeks was acheived by 53.6% (95% CI [39.6% to 67.5%]) of pts which was sustained over the 8-week dosing interval. Treatment with ULTOMIRIS resulted in reduced thrombocytopenia, haemolysis and improved kidney function. The safety profile was consistent with that observed in two PIII studies in pts with paroxysmal nocturnal hemoglobinuria (PNH) [4].
Apr 18Both PIII studies are still recruiting [2].
Jul 17PIII study to evaluate ALXN1210 in 16 children and adolescent patients with aHUS naïve of treatment with complement inhibitor starts (NCT03131219). Recruitment is taking places in several countries including US & EU. Primary outcome is complete TMA response; collection of these data is due to complete Dec 18 [2].
Nov 16PIII study to evaluate ALXN1210 in 55 adult and adolescent patients with aHUS naïve of treatment with complement inhibitor starts (NCT02949128). Recruitment is taking places in several countries including US & EU (inc. UK). Primary outcome is complete TMA response; collection of these data is due to complete Nov 18 [2].

Evidence based evaluations

UltomirisParoxysmal nocturnal haemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) - 100mg/ml (advanced) IV formulation

Information

Ultomiris
New formulation
Alexion
Alexion

Development and Regulatory status

Recommended for approval (Positive opinion)
Recommended for approval (Positive opinion)
Approved (Licensed)
Yes
Yes
Oct 20Launched in US. A decision is expected in EU in November [6].
Oct 20FDA has approved ravulizumab 100 mg/mL formulation for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) and for atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy for adult and pediatric (one month of age and older [5].
Sep 20UK launch plans for this formulation are unknown, but is likely to be affected by NICE decisions on approval for use in aHUS and PNH, which are still pending. The TA for aHUS has now been rescheduled into the work programme and is due to be discussed at committee on 13 April 2021; the TA for PNH is due to be discussed earlier at committee on 10 March 2021 [4].
Sep 20The CHMP has recommended marketing authorization in the EU for a new 100 mg/mL intravenous (IV) advanced formulation of Ultomiris. Ultomiris is administered every eight weeks for the treatment of PNH and aHUS. Ultomiris 100 mg/mL would constitute an advancement in the treatment experience for patients with aHUS and PNH by reducing average annual infusion times by approximately 60% compared to Ultomiris 10 mg/mL while delivering comparable safety and efficacy. With Ultomiris 100 mg/mL, most patients will spend six hours or less a year receiving treatment. The European Commission decision is anticipated in Nov 20 [3].
Sep 20Positive opinion from CHMP [1].

Category

Long-acting C5 complement inhibitor.
PNH is a rare disease where haemolytic anaemia occurs due to the action of complement on erythocyte call membranes. aHUS or atypical hemolytic uremic syndrome (also rare) involves complement-mediated thrombotic microangiopathy resulting in haemolysis [2].
Paroxysmal nocturnal haemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) - 100mg/ml (advanced) IV formulation
Intravenous

UltomirisParoxysmal nocturnal haemoglobinuria (PNH) in children and adolescents

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor
PNH is a very rare acquired bone marrow disorder characterised by intravascular haemolysis, with resultant anaemia; before effective treatments were available, median survival was 10 years from diagnosis and half of those affected died from complications. Spontaneous recovery may occur, but only in a minority of patients. [2] UK incidence is about 0.13/100,000/year and 15-year prevalence is likely to be around 1.59/100,000 [3].
Paroxysmal nocturnal haemoglobinuria (PNH) in children and adolescents
Intravenous

Evidence based evaluations

UltomirisNeuromyelitis optica spectrum disorder (NMOSD) in adults

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

First in class, humanised monoclonal antibody C5 complement inhibitor
Neuromyelitis Optica is a rare disorder affecting eyes and spinal cord leading loss of vision, mobility, and sensation. 90% of patients have relapsing NMO. It affects about 0.4 in 10,000 people in the EU equivalent to a total of around 20,000 people.
Neuromyelitis optica spectrum disorder (NMOSD) in adults
Intravenous

UltomirisGeneralised myasthenia gravis in adults

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

First in class, humanised monoclonal antibody C5 complement inhibitor
The incidence ranges from 0.3 to 2.8 per 100,000. It is estimated to affect more than 700,000 people worldwide. The prevalence of MG in the UK is estimated at about 15 per 100,000 population. Peak incidence is in the third decade for women and the sixth or seventh decade in men [1].
Generalised myasthenia gravis in adults
Intravenous

Ultomiris Atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria - SC formulation

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor
Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterised by hemolytic anemia, thrombocytopenia and uremia. In Europe, the disorder affects ~0.11 per 1 million individuals aged 0-18 years. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder that affects between 0.5-1.5 per million people in the general population [3].
Atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria - SC formulation
Subcutaneous injection

Ultomiris Amyotrophic lateral sclerosis (motor neurone disease) in adults

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor
MND is relatively uncommon with an annual incidence of about 2 cases per 100,000 population. Prevalence is about 5-7 per 100,000. General practitioners can expect to see one or two cases in their career. It can occur at any age but is more common in people aged over 50. The male to female ratio is 2:1 [1].
Amyotrophic lateral sclerosis (motor neurone disease) in adults
Intravenous infusion

UltomirisHaematopoietic stem cell transplant-related thrombotic microangiopathy (HCST-TMA)

Information

Ultomiris
Licence extension / variation
Alexion
Alexion

Development and Regulatory status

None
Phase III Clinical Trials
None

Category

Long-acting humanised monoclonal antibody C5 complement inhibitor. Weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 4 to 8 weeks.
An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment [1].
Haematopoietic stem cell transplant-related thrombotic microangiopathy (HCST-TMA)
Intravenous infusion