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39225711000001103

New Medicines

Treprostinil Tillomed Idiopathic or heritable pulmonary arterial hypertension (PAH) - intravenous/subcutaneous formulation

Information

Treprostinil Tillomed
New molecular entity
Tillomed
Not Known

Development and Regulatory status

Launched
None
None
November 2020
Aug 21New strengths available 100MG/20ML x 1 £7,407.00, 200MG/20ML x 1 £8,999.00, 20MG/20ML x 1 £2,499.00 [7].
Nov 20Launched in the UK. Pack sizes and prices 50mg/20ml x 1 £4,062, 1000mg/20ml x 1 £7,407 [6].
Sep 20UK Launch is planned for October 2020 [4].
Jul 20Treprostinil sodium solution for infusion was approved by the MHRA -the full indication is treatment of idiopathic or heritable pulmonary arterial hypertension (PAH) to improve exercise tolerance and symptoms of the disease in patients classified as New York Heart Association (NYHA) functional class III [1,2,3].

Category

Prostacyclin analogue that has a direct vasodilation effect on the pulmonary and systemic arterial circulation and inhibits platelet aggregation.
In its pure idiopathic form pulmonary hypertension is a rare disease with an approximate annual incidence of about 1–3.3 cases per million population [5].
Idiopathic or heritable pulmonary arterial hypertension (PAH) - intravenous/subcutaneous formulation
Intravenous infusion and
Subcutaneous infusion

Evidence based evaluations

Idiopathic or heritable pulmonary arterial hypertension (PAH) - intravenous/subcutaneous formulation

Information

New formulation
Dr Reddys Laboratories
Not Known

Development and Regulatory status

Launched
None
None
April 2021
Sep 21Company confirms UK launch did happen in April 2021 [8].
Sep 21Treprostinil solution for infusion available in the UK (and possibly has been since Apr 21). NHS indicative price for one 100mg/20ml vial is £6,222.50; one 200mg/20ml vial is £11,417.50; one 50mg/20ml vial is £2,998.75 [7].
Dec 20UK launch planned February 2021 [6].
Apr 20UK launch is planned in July 2020 [5].
Feb 20Treprostinil sodium solution for infusion was approved by the MHRA -the full indication is treatment of idiopathic or heritable pulmonary arterial hypertension (PAH) to improve exercise tolerance and symptoms of the disease in patients classified as New York Heart Association (NYHA) functional class III [1,2,3,4].

Category

Prostacyclin analogue that a direct vasodilation effect on the pulmonary and systemic arterial circulation and inhibits platelet aggtegation.
In its pure idiopathic form pulmonary hypertension is a rare disease with an approximate annual incidence of about 1–3 cases per million population.
Idiopathic or heritable pulmonary arterial hypertension (PAH) - intravenous/subcutaneous formulation
Subcutaneous infusion and
Intravenous infusion

Evidence based evaluations

TrepulmixChronic thromboembolic pulmonary hypertension - subcutaneous formulation

Information

Trepulmix
New formulation
AOP Orphan Pharmaceuticals
Not Known

Development and Regulatory status

Licensed but not launched
Launched
None
Yes
Nov 21Trepulmix is available in Spain, and potentially also in other EU countries including Germany, Italy and Latvia (or soon to be) [10,11].
Apr 20Approved in EU, as liquid in a vial for direct subcutaneous infusion, undiluted. Multi dose vials at 4 difference concentrations will be available [9].
Jan 20Recommended for EU approval by CHMP - the full indication is "Treatment of adult patients with WHO Functional Class (FC) III or IV and: inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after surgical treatment, to improve exercise capacity.” Treatment should be started and monitored only by clinicians experienced in the treatment of pulmonary hypertension. Treatment should be started under close medical supervision in a medical facility where intensive care can be provided [8].
Jan 20Still pre-registration in the EU for treatment of CTEPH. At the meeting on 27-30 January, the CHMP will consider a list of Outstanding Issues (adopted on 12.12.2019) and a list of Questions (adopted on 27.06.2019) [7].
Mar 19Filed in the EU via the centralised procedure [6].
Sep 18The IV formulation of treprostanil was under regulatory review by the CHMP; however, the application was withdrawn by SciPharm Sarl as they were unable to supply additional study data requested by the CHMP within the required timeframe [4].

Category

Prostacyclin analogue that dilates blood vessels, prevents platelet aggregation and prevents proliferation of smooth muscle cells surrounding blood vessels
Chronic thromboembolic pulmonary hypertension is a type of pre-capillary pulmonary hypertension, resulting from incomplete resolution of pulmonary embolism. It affects 0.5-3% of patients post-pulmonary embolism and has an annual incidence between 1-7 cases per million population [2,3].
Chronic thromboembolic pulmonary hypertension - subcutaneous formulation
Intravenous &
Subcutaneous

Further information

Yes

Trial or other data

Nov 18NHS England current clinical commissioning policy (issued Jun 14) states that treprostinil will not be routinely commissioned for new patients but funding will continue for patients already established under the terms of the national policy. While it may have a role in the subcutaneous treatment of very small numbers of seriously ill patients with PH who are not suitable for nebulised or intravenous administration of a prostanoid, commissioners believe that, at around 3-4 times the price of equivalent alternatives, its pricing structure cannot be justified [5].
Nov 18PIII trial to evaluate the efficacy and tolerability of two doses of SC treprostinil in patients with severe inoperable chronic thromboembolic pulmonary hypertension published (NCT01416636; N=105). Treprostinil resulted in an improvement from baseline in mean 6-min walk distance in the high-dose (target 30 ng/kg per min at week 12) and low-dose (target 3 ng/kg per min at week 12) groups (44.98 m and 4.29 m respectively; p=0.0016) [1].

Evidence based evaluations

TrevyentPulmonary arterial hypertension (PAH) - subcutaneous infusion

Information

Trevyent
New formulation
Correvio
United Therapeutics Limited

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Yes
Yes
Jan 21United Therapeutics meets US FDA to discuss deficiencies noted in the complete response letter and announces intention to resubmit the NDA in 2022 [18]
Jul 20FDA issued a complete response letter indicating that some of the deficiencies previously raised by had not yet been addressed to its satisfaction. United expect to resubmit in 2021 [17].
Sep 19Correvio expects to file regulatory submissions for Trevyent in Europe in mid-2020 [15].
Sep 19United Therapeutics announce FDA has accepted NDA for Trevyent for the treatment of PAH for review with a target PDUFA date of 27/4/20 [14].
Jun 18Plans continue for a MAA for Trevyent to be filed in Europe, shortly after SteadyMed filing an NDA in the US [12].
Jun 18United Therapeutics, which is developing treprostinil diethanolamine (Orenitram), acquires SteadyMed. SteadyMed has previously signed an exclusive license and supply agreement with Cardiome Pharma Corp (now Correvio) for commercialization of Trevyent in Europe [11].
May 18SteadyMed announces it plans to resubmit the Trevyent NDA and, subject to review by the Agency, have it accepted for filing by the end of 2018 [10].
Dec 17SteadyMed reported that it agreed with the FDA the work necessary for the resubmission and acceptance of the NDA. No further clinical trials are required and the company expects both NDA submission and acceptance for PAH by end of 2018 [8].
Aug 17The FDA has refused to accept the NDA filing, based on a preliminary review that concluded that the application is not sufficiently complete to allow full review. It has requested further data on a number of aspects. The company believe that the issues raised can be addressed and will request a meeting with the FDA for clarification [7].
Jul 17NDA submitted to US FDA for treatment of pulmonary arterial hypertension [6].
Apr 17Cardiome plan EU filing for 2017 and launch 2018 [5].
Jan 17Has orphan status in the US [4].
Jan 17SteadyMed announces its intention to file for NDA application for approval of treprostinil patchpump for the treatment of pulmonary arterial hypertension in Q2 17 and expected launch in late 2017 in the US [4].
Jun 16SteadyMed holds a pre-NDA meeting with FDA, confirming the requirements for the 2017 submission of a NDA for treprostinil patch pump [4].
Jan 16SteadyMed announces that Trevyent will be submitted to the EMA under the centralised review procedure for the EU/EEA market; marketing in Europe (also Canada and Middle East) will be via Cardiome / Correvio International. FDA submission expected Q3 2016 [3].
May 15SteadyMed submits application for Orphan Drug Designation for Trevyent for Pulmonary Arterial Hypertension [1].

Category

Prostacyclin agonist. Trevyent combines SteadyMeds PatchPump technology with treprostinil. PatchPump is a disposable, parenteral drug administration platform that is prefilled and preprogrammed to release the drug at a specific rate [2].
In its pure idiopathic form pulmonary hypertension is a rare disease with an approximate annual incidence of about 1–3 cases per million population.
Pulmonary arterial hypertension (PAH) - subcutaneous infusion
Subcutaneous infusion

Trial or other data

Jul 15SteadyMed reports that it has completed its two-year programme of human factor studies for treprostinil patchpump. The programme was initiated in 2013 and included eight studies in a total of 148 subjects, including 92 patients with pulmonary arterial hypertension, 33 healthcare providers and 23 additional subjects, in the US, Canada, Middle east and the Europe. The studies, which are required for approval of drug-device combination products, validated the usability of the treprostinil patchpump in pulmonary arterial hypertension [4].

TyvasoPulmonary hypertension associated with interstitial lung disease (incl. combined pulmonary fibrosis and emphysema) - inhaled solution formulation

Information

Tyvaso
New formulation
United Therapeutics Limited
United Therapeutics Limited

Development and Regulatory status

None
None
Launched
Yes
Apr 21Tyvaso launched in US [9].
Apr 21US FDA has approved treprostinil Inhalation Solution for the treatment of patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability [7].
Jan 21In its latest annual report, United Therapeutics states it is evaluating whether the INCREASE results could support marketing applications outside the US. The company currently markets the IV/SC Remodulin formulation of treprostinil in most major European markets except the UK and Spain; it does not market Tyvaso in any European country [6].
Dec 20Granted orphan drug status in US [4].
Aug 20The FDA has accepted a new drug application for this indication based on the results of the INCREASE study [3].

Category

Long-acting prostacyclin (epoprostenol) analogue in an inhaled solution formulation
Interstitial lung diseases (ILD) comprise a broad spectrum of conditions; together these conditions affect between 1,500 and 3,000 individuals in England each year [1]. 20-40% of patients with ILD have pulmonary hypertension [2].
Pulmonary hypertension associated with interstitial lung disease (incl. combined pulmonary fibrosis and emphysema) - inhaled solution formulation
Inhalation

Trial or other data

Jul 21Post-hoc analysis of PIII INCREASE study (n=326) found inhaled treprostinil was associated with an improvement in FVC of 1.8% vs placebo at both 8 and 16 weeks (both p<0.05). Subgroup analysis found the improvement was most evident in those with idiopathic interstitial pneumonia [8].
Jan 21PIII INCREASE study (NCT02630316) is published; the RCT (n=326) found inhaled treprostinil improved exercise capacity from baseline, assessed with 6-minute walk test, as compared with placebo at week 16 (least-squares mean difference 31.12m; 95% CI 16.85-45.39; p<0.001). Clinical worsening occurred in 22.7 vs. 33.1%, respectively [5].

Tyvaso DPI Pulmonary hypertension associated with interstitial lung disease and pulmonary arterial hypertension - dry powder inhaler formulation

Information

Tyvaso DPI
New formulation
United Therapeutics Limited
United Therapeutics Limited

Development and Regulatory status

None
None
Approved (Licensed)
May 22FDA approves Tyvaso DPI (treprostinil) inhalation powder for the treatment of PAH (WHO Group 1) and pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. Tyvaso DPI is the only dry powder inhaler approved by the FDA for use in PAH and PH-ILD. Company plans to launch in the US in June 2022 [11,12].
Feb 22FDA requests additional information from United Therapeutics Corporation concerning the pulmonary safety of treprostinil DPI related to a pending Citizen Petition. United Therapeutics Corporation promptly responded to the request, and the FDA indicated that the response constitutes a major amendment to the treprostinil dry powder inhalation NDA, which extended the anticipated deadline to review the pending NDA to May 22 [9].
Dec 21United Therapeutics Corporation resubmits NDA, and the FDA issued an action date for Feb 22 [9].
Oct 21United Therapeutics receives complete response from the US FDA citing a single deficiency preventing approval, related to an open inspection issue at a third-party facility that performed analytical testing of treprostinil. They also stated their intention to launch treprostinil DPI post approval no later than the summer of 2022 [8]
Jun 21FDA accept for priority review MannKind’s and United Therapeutics’ New Drug Application (NDA) for Tyvaso DPI™, a treatment for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD).[7]
Oct 20United Therapeutics intends to file to the FDA data from two studies (combined with long-term stability studies of the DPI product) to support their treprostinil Technosphere dry powder inhaler., which it licensed from MannKind Corporation. The BREEZE study (NCT03950739) and a second clinical study in healthy volunteers to compare the pharmacokinetics of Treprostinil Technosphere to Tyvaso [3].

Category

Prostacyclin vasodilator in a dry powder inhaler.
Interstitial lung diseases (ILD) comprise a broad spectrum of conditions; together these conditions affect between 1,500 and 3,000 individuals in England each year [5]. 20-40% of patients with ILD have pulmonary hypertension [6].
Pulmonary hypertension associated with interstitial lung disease and pulmonary arterial hypertension - dry powder inhaler formulation
Inhalation

Trial or other data

Apr 22Additional clinical and long-term safety data from the PI BREEZE study published in the journal Pulmonary Circulation. The publication evaluated the BREEZE study and its ongoing optional extension phase (OEP), and concluded: Tyvaso DPI’s delivery device, along with the clinical results from BREEZE, may facilitate the introduction of inhaled treprostinil earlier in the clinical course of PAH for appropriate patients; Doses of Tyvaso DPI above the current recommended dose of nebulized Tyvaso (9-12 breaths four times daily) were well tolerated, potentially allowing for titration to higher dose levels without resulting in prolonged treatment sessions; A simplified dosing regimen could potentially increase patient compliance; and Tyvaso DPI has a pharmacokinetic (PK) profile comparable to nebulized Tyvaso, such that patients will not have to use more drug than nebulized Tyvaso to get the same treprostinil blood concentration or treatment effect [10].
Feb 21The PI BREEZE study (NCT03950739) has only been recruiting in the US and is assessing a combination drug-device product which is comprised of a dry powder formulation of Treprostinil Inhalation Powder (TreT) and a small, portable, dry powder inhaler. In this safety and tolerability study, patients with PAH on a stable dose of Tyvaso (6 to 12 breaths 4 times daily [QID]) will be evaluated after switching to a corresponding dose of TreT. Patients will undergo PK assessments, safety assessments, a 6-Minute Walk Test (6MWT), and questionnaires for satisfaction/preference for inhaled devices and patient-reported PAH symptoms and impact. Following 3 weeks of treatment with TreT, patients will be offered the opportunity to participate in the Optional Extension Phase until the study terminates or the drug/device becomes commercially available [4].
Jan 21BREEZE study of Tyvaso DPI (inhaled dry powder treprostinil) met its primary objective of demonstrating safety and tolerability in patients with pulmonary arterial hypertension (PAH) transitioning from nebulised treprostinil Inhalation Solution [1].