Date: 2016-04-07
Type of information: Granting of a Market Authorisation in the EU
Product name: Rhucin®/Ruconest®
Compound: recombinant human C1 inhibitor - conestat alfa
Therapeutic area: Rare diseases - Genetic diseases
Action mechanism: enzyme inhibitor. Ruconest® (conestat alfa) is a human recombinant C1-esterase inhibitor purified from the milk of transgenic rabbits. Hereditary angioedema, which is caused by having insufficient amounts of a C1-esterase inhibitor, affects approximately 6,000 to 10,000 people in the United States. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract, or airway. These acute attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection. Swelling of the airway is potentially fatal without immediate treatment. Ruconest® is intended to restore the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling.
Company: Pharming (The Netherlands), Santarus, now Salix Pharmaceuticals (USA - NC)
Disease: acute attacks of Hereditary Angioedema (HAE) hereditary angioedema attacks in adolescents with HAE
Latest news: * On April 7, 2016, Pharming Group announced that the European Commission adopted the CHMP recommendation to include the treatment of hereditary angioedema attacks in adolescents with HAE and to remove the requirements for rabbit IgE testing that formed part of the EU label for Ruconest®. The CHMP also noted that the importance of favourable effects of Ruconest® is further supported by the continued availability of supply of Ruconest® (produced by recombinant technology) in comparison to supply from blood donor plasma that may vary and not being a blood derived product thereby removing the potential risk of exposure to blood borne pathogens. * On December 21, 2015, Pharming Group and its partner, HyupJin Corporation, a Seoul based South Korean specialty pharma company, announce that Hyupjin has received the marketing authorisation for Ruconest® (recombinant human C1 inhibitor) in South Korea. Ruconest® is approved for the treatment of acute angioedema attacks in adult patients with hereditary angioedema HAE. Effectiveness was not established in HAE patients with laryngeal and oro-pharyngeal attacks. HyupJin will now seek reimbursement for Ruconest® in South Korea. * On December 7, 2015, Pharming announced that the European Medicines Agency (“EMA”) has recently renewed the marketing authorization for Ruconest® for an unlimited period. Ruconest® was first approved by the EMA in 2010 for the treatment of acute attacks of Hereditary Angioedema. Such initial marketing authorisation is normally issued initially for five years, and reviewed for extension after these first five years. The recommendation of the Committee for Medicinal Products for Human Use (CHMP) for renewal of the marketing authorization is based on the positive patient benefit-risk profile for Ruconest® for the treatment of HAE attacks. * On October 8, 2015, Pharming Group and Salix Pharmaceuticals announced that the FDA has granted 12 years of exclusivity to Ruconest® (C1 esterase inhibitor [recombinant]) 50 IU/kg. The determination of exclusivity ensures that FDA will not approve before July 16, 2026 any applications for biosimilars of Ruconest®— i.e. applications for recombinant C1 esterase inhibitors referencing Ruconest® submitted under section 351(k) of the Public Health Service Act under the framework established by the Biologics Price Competition and Innovation Act of 2009. Under the Biologics Price Competition and Innovation Act of 2009, exclusivity for licensed biologics can be granted for a 12-year period from the date of first licensure of the product. Ruconest® was approved by the FDA on July 16, 2014, for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). Effectiveness was not established in HAE patients with laryngeal attacks. The drug is contraindicated in patients with a history of allergy to rabbits, or rabbit-derived products, and patients with a history of life-threatening immediate hypersensitivity reactions to C1 esterase preparations, including anaphylaxis. * On November 3, 2014, Pharming Group and Salix Pharmaceuticals announced the launch of Ruconest® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kg in the United States for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). Effectiveness in clinical studies was not established in HAE patients with laryngeal attacks. Ruconest® is available by prescription across the United States through RUCONEST SOLUTIONS and comes with comprehensive patient support services. Ruconest® is manufactured by Pharming Group NV in the Netherlands. Salix has licensed exclusive rights from Pharming to commercialize Ruconest® in North America and market RUCONEST for the treatment of acute HAE attack symptoms. * On July 16, 2014, the FDA approved Ruconest®, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema.The safety and efficacy of Ruconest® was evaluated in a multicenter controlled clinical trial. Forty-four adult and adolescent patients with acute attacks were treated with Ruconest®. The most common adverse reactions reported in patients treated with Ruconest were headache, nausea and diarrhea. Ruconest® received orphan-drug designation for acute attacks by the FDA because it is intended for treatment of a rare disease or condition. Ruconest® is manufactured by Pharming Group NV, Leiden, the Netherlands, and will be distributed in the United States by Santarus Inc., a wholly owned subsidiary of Salix Pharmaceuticals Inc., Raleigh, North Carolina. Salix is preparing to launch Ruconest® during 4Q 2014. A $20 million milestone payment from Salix will become payable within 30 days after the first commercial sale of Ruconest® in the US or within 90 days since FDA approval.
This will mean that, effective now, adolescents also have access to (non- blood derived) recombinant C1- inhibitor therapy for the treatment of their angioedema attacks. In addition, the requirement to test HAE patients for pre-existing antibodies against rabbit dander, prior to treatment with Ruconest® and following each tenth treatment with Ruconest®, has been removed from the label. The requirement for IgE testing was a specific EU request based on a single adverse drug reaction in a study subject. The need for testing was not required in the US as more safety data were available at the time of the Biologics License Application (BLA) and subsequent FDA-approved label in 2014. The EU patient information leaflet will be updated to reflect these changes over the coming months.
* On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive
opinion recommending a change to the terms of the marketing authorisation for Ruconest® (conestat alfa). The CHMP adopted an extension to the existing indication as follows: “Ruconest® is indicated for treatment of acute angioedema attacks in adults and adolescents with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency.”
In addition, Pharming reports that RUCOVITAE, the Company’s patient support programme, is now available to eligible HAE sufferers in Austria, Germany and the Netherlands. RUCOVITAE aims to provide patients with timely on-demand therapy at their home or other specified location to assist them in dealing with their HAE disease and optimize their HAE treatment. The on-demand, on-location care services are provided in Germany and Austria by homecare organisation Atlantis Healthcare Deutschland GmbH and in the Netherlands by Dutch homecare organisation Eurocept B.V. through their country-wide networks of community-based specialised nurses. Eligible HAE patients can enrol in RUCOVITAE through their physician.* On February 24, 2014, Pharming and Salix Pharmaceuticals (Salix has completed Santarus acquisition in January 2014) have announced that the FDA has extended the Prescription Drug User Fee Act (PDUFA) Action Date to July 16, 2014 for theBiologics License Application (BLA) for Ruconest® (recombinant human C1 esterase inhibitor) 50 IU/kg. Pharming and Salix are seeking U.S. marketing approval of Ruconest® for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE).* On January 15, 2014, Pharming Group has announced that its partner, MegaPharm, a privately owned Israeli pharmaceutical company, has received marketing approval for Ruconest® (recombinant human C1 inhibitor) in Israel. The indication as approved is for the treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency. Alongside, Ruconest® was approved by the reimbursement committee, to be added on the Israel Health basket with no extra costs. Under the agreement, MegaPharm will purchase its commercial supply of Ruconest® from Pharming at a supply price based on a percentage of net sales. The number of HAE patients in Israel is estimated at approximately 250. MegaPharm anticipate launching Ruconest® during Q1 of this year.* On June 18, 2013, Santarus and Pharming Group have announced that the FDA has accepted for filing the Biologics License Application (BLA) for Ruconest® (recombinant human C1 esterase inhibitor) 50 IU/kg for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The FDA indicated that as part of its review it plans to present the BLA to the Blood Products Advisory Committee. Pursuant to the Prescription Drug User Fee Act (PDUFA) guidelines, Santarus and Pharming expect the FDA will complete its review or otherwise respond to the Ruconest® BLA by April 16, 2014. Santarus licensed certain exclusive rights from Pharming to commercialize Ruconest® in North America for the treatment of acute attacks of HAE as well as other potential future indications. Under the terms of the license agreement, a $5 million milestone is payable to Pharming as a result of the FDA acceptance for review of the BLA for Ruconest® .* On April 17, 2013, Pharming Group and Santarus have announced the submission of a Biologics License Application (BLA) to the FDA to obtain marketing approval for Ruconest® (recombinant human C1 esterase inhibitor) 50 U/kg, an investigational drug for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). The safety and efficacy of Ruconest® for the treatment of HAE attacks were evaluated in a clinical program that included a Phase III randomized placebo-controlled study conducted under a Special Protocol Assessment agreement with the FDA. The Ruconest® clinical program also included two additional randomized placebo-controlled studies and four open label treatment studies. In total, the BLA dossier includes ten clinical studies covering 940 administrations in 236 subjects. * On August 31, 2011, Pharming and Swedish Orphan Biovitrum announced that Ruconest® is now being launched in Pharming’s home market the Netherlands. The launch follows immediately after final approval to make Ruconest® available was received from the Dutch regulatory authority (College ter Beoordeling van Geneesmiddelen). To date Ruconest® is available in Sweden, Norway, Denmark, UK, Germany, France, Latvia and the Netherlands. Reimbursement applications are under review in most of the other countries; the European roll-out by SOBI continues. * On May 5th, 2011, Pharming announced that following discussions with the FDA, Pharming and its U.S. commercialization partner, Santarus, have submitted an amendment to the protocol for the Rhucin® Phase III clinical study into which the first patient was enrolled in February 2011. Based on input from the FDA and from the FDA meeting minutes, the amendment to the protocol, includes an increase of the number of patients from 50 to approximately 75 and a modification to the manner in which the primary endpoint will be assessed. This modification eliminates the need for further validation of the visual analog scale. Pharming still anticipates that the Phase III study will be completed within 12 to 18 months from its original initiation. * On February 28, 2011, Pharming and Santarus have announced the receipt of a “refusal to file” letter from the FDA for the Rhucin® (recombinant human C1 inhibitor) Biologics License Application (BLA) submitted by Pharming. In the letter the FDA indicated that the BLA was not sufficiently complete to enable a critical medical review. In reaching its conclusion, the FDA indicated that the previously conducted studies evaluating Rhucin® for the treatment of acute attacks of Hereditary Angioedema (HAE) did not provide data for a sufficient number of subjects to support the proposed dose of 50 U/kg and lacked prospectiv e validation of the visual analog scale used in measuring the clinical effects of Rhucin®. The FDA also provided other comments on the prior clinical studies and indicated that they will provide additional feedback on the design of the ongoing Phase IIIb clinical study, which had been initiated based on previous discussions with the FDA. In addition, the FDA requested that the results of the Phase IIIb clinical study be included in any future BLA submission for Rhucin®. The FDA has the ability to formally file or refuse to file an application within 60 days of the completion of the submission, which occurred in late December 2010. Both companies intend to meet with the FDA at the earliest opportunity to discuss the issues raised in the FDA letter and to reach a more comprehensive understanding of what would be required for the BLA to be accepted for review.
Patents: * On December 12, 2011, Pharming has announced that the United States Patent and Trademark Office (USPTO) has granted the Company U.S. Patent 8,071,532, covering a method of preventing, reducing or treating an ischemia and/or reperfusion injury by administering recombinant C1 inhibitor (Ruconest®/ Rhucin®). The broad claims in the patent provide protection until 2028. This is Pharming's first patent granted on ischemia/reperfusion injury in the U.S., and represents a significant milestone in the continuing development of the Company's C1 inhibitor franchise in additional indications associated with reperfusion injury such as Delayed Graft Function (DGF) and Acute Myocardial Infarction (AMI). The patent relates to a novel method of using recombinant C1 inhibitor (rhC1 INH), being produced either in cell cultures or in transgenic animals, wherein rhC1 INH is administered after the onset of ischemia or the start of reperfusion. Recombinant C1 inhibitor showed - in contrast to plasma-derived C1 inhibitor - to be still therapeutically active in a time span of 6 hours and therefore particularly useful for unforeseen occurrences of ischemic reperfusion such as stroke and myocardial infarction, whereas other claims are directed to treatment during organ transplantations.
Submission of marketing authorization application USA : 2013-04-17
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2014-07-16
UE authorization: 2010-10-28
Favourable opinion UE: 2010-06-24
Favourable opinion USA:
Orphan status USA: 1999-02-23
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
