April CHMP Meeting: Disappointment In Advance For AB Science, Gilead Hopeful On Biktarvy
Executive Summary
Just four products are listed as being up for an opinion on whether they should be approved for sale across the EU at the latest meeting of the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), under way this week in London.
The CHMP has already adopted a negative opinion on one of the four marketing authorization applications in question – AB Science’s would-be amyotrophic lateral sclerosis (ALS) treatment, Alsitek (masitinib) – so that leaves three: Gilead Sciences’s fixed-dose combination therapy for HIV, bictegravir/emtricitabine/tenofovir alafenamide (approved in the US in February this year as Biktarvy (Also see "Gilead's Biktarvy Approval Heightens HIV Competition With ViiV" - Scrip, 7 Feb, 2018.)), and two generics – sufentanil and carmustine.
The sufentanil product could be AcelRx Pharmaceuticals’s Dsuvia, for the management of moderate to severe pain. The company recently ran into problems in the US with its filing for the product there. (Also see "Keeping Track: FDA Hands Out Complete Responses, Expedited Pathway Designations" - Pink Sheet, 15 Oct, 2017.)
Yet Another Masitinib Blow For AB Science
The CHMP's rejection of the MAA for Alsitek means that AB Science has now failed to get masitinib approved in several indications. The French company will ask the CHMP to re-examine this latest negative opinion, adopted on April 18.
The EMA’s notice on the refusal of the marketing authorization for Alsitek cites the grounds for refusal as follows:
“The applicant presented the results of one main study involving 394 patients with ALS, where Alsitek was compared with placebo (a dummy treatment), both taken together with riluzole. The main measure of effectiveness was the change in the patients’ symptoms after 48 weeks of treatment, assessed using a standard scale for ALS. The CHMP concluded that the main study in patients with ALS did not show that Alsitek is effective at slowing down progression of the disease. Although a positive effect on symptoms was seen in the group of patients whose disease worsened at a normal rate compared with those whose disease worsened rapidly, the CHMP considered that this way of classifying patients was arbitrary and did not reflect clinical practice.
In addition, there was no reason why the medicine would work in one group of patients and not in others.
Furthermore, an inspection at two of the study sites showed deficiencies in the way the study was conducted, which cast doubt on the integrity of the data.
Finally, the Committee was concerned about the way data from patients who withdrew from treatment were handled, which could have biased the results in favour of Alsitek. Therefore, the CHMP was of the opinion that the study did not provide reliable evidence on the benefits of Alsitek and recommended that it be refused marketing authorisation.”
AB Science says it “reaffirms its commitment to carry out the development of masitinib in ALS in order to provide a new treatment option to patients” and that, in order to address the grounds for refusal, it will provide further analyses on each of the points as part of the re-examination procedure. It expects the result of the re-examination should be announced in July.
In an unusual move, the CHMP agreed the negative opinion on the MAA for Alsitek via written procedure between scheduled meetings. A written procedure is sometimes used by the committee between scheduled meetings after approval of the chairperson, the EMA explained. The agency told the Pink Sheet: “The CHMP discussed Alsitek at its March meeting and agreed that the benefit-risk balance was negative. However, the opinion could not be adopted because the grounds for the refusal were not completely ready at the time; therefore the final opinion was agreed via written procedure.”
Making recommendations on whether products that have been through the centralized procedure should be approved for sale is one of the many things the CHMP does at its monthly meetings; this latest meeting runs from April 23-26. The committee’s opinions are forwarded to the European Commission for a legally binding decision valid throughout the EU. The commission usually follows CHMP recommendations and generally makes its decision within 67 days.
Eteplirsen
A handful of companies with marketing authorization applications (MAAs) at the final stages of the centralized drug evaluation procedure are scheduled to appear before the CHMP to answer concerns the committee still has regarding their applications.
One such company is AVI Biopharma/Sarepta Therapeutics, and the MAA in question relates to the controversial orphan drug, eteplirsen, for the treatment of Duchenne muscular dystrophy. Eteplirsen was approved as Exondys 51 in the US in September 2016 after an extremely contentious and very public debate within the Food and Drug Administration over the approvability of the product. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)
According to the CHMP meeting agenda, AVI was scheduled to appear before the CHMP on April 24. An opinion on whether the product should be approved was not expected to be adopted, the EMA confirmed. The CHMP adopted a Day 180 list of outstanding issues (LoOI) relating to the product in December 2017. (Also see "‘Outstanding Issues’ Near For Products Approaching EU Review End – Including Neulasta Biosimilar" - Pink Sheet, 15 Dec, 2017.)
The sponsor of another product in the late stages of the centralized procedure – a ciclosporin product for the treatment of moderate dry eye disease in adults – was also scheduled to appear before the committee. In this case, there had been two LoOIs, one adopted in September 2017 and the other in February 2018.
LoOIs
LoOIs are adopted when new drugs have reached day 180 of the up to 210-day assessment period (or day 120 of the up to 150-day assessment period for products undergoing accelerated assessment). They are usually an indication that a CHMP opinion on marketing authorization is due in the following months.
The CHMP is due to adopt LoOIs this week for a total of 17 products. The products include six orphan therapies for rare or ultra-rare diseases, including Akcea Therapeutics’ volanesorsen for familial chylomicronemia syndrome, Ionis Pharmaceuticals Inc.’s inotersen for the treatment of transthyretin amyloidosis (hATTR), and Kite Pharma Inc.’s CAR T therapy, axicabtagene ciloleucel (approved as Yescarta in the US) for various aggressive forms of lymphoma. (Also see "EU CAR-T Race Tightens After Yescarta Reverts To Standard Review" - Pink Sheet, 23 Apr, 2018.)
Other drugs due for an LoOI include Novartis AG’s Aimovig (erenumab) for migraine prophylaxis, Lilly Research Laboratories’s Verzenio (abemaciclib) for breast cancer, and a paclitaxel product for ovarian cancer, as well as four more biosimilar versions of AbbVie’s Humira (adalimumab) and one of Roche’s Herceptin (traztuzumab). Several companies with products at this stage are scheduled to appear before the CHMP to provide oral explanations. (This will be covered in a future Pink Sheet article.)
The carmustine product which is up for an opinion this week on whether it should be approved has had three LoOIs over the course of its review - these were adopted in July and October 2017 and also in February 2018. The sponsor is seeking approval of carmustine for the treatment of brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin’s lymphomas.
Re-examination action
There will also be action at the meeting concerning two products that received a negative opinion in recent months and where the companies have requested a re-examination of the decision. The products are Portola Pharmaceuticals’s Dexxience (betrixiban) for preventing venous thromboembolism and Radius Health’s Eladynos (abaloparatide), for the treatment of osteoporosis. The action includes the appointment of re-examination rapporteurs and the adoption of a draft timetable for the re-examination. (Also see "Six New Drugs Get EMA Nod, Radius and Portola To Fight Rejections" - Pink Sheet, 23 Mar, 2018.)
Re-examinations very rarely result in the CHMP coming to a different decision.
MAA Withdrawal
Also according to the meeting agenda, Lucane Pharma, a French company acquired by EuroCept Pharmaceuticals in October 2017, is withdrawing its initial MAA for its orphan-designated sodium benzoate product, intended for the treatment of “non ketotic hyperglycinemia, urea cycle disorders including carbamoyl-phosphate synthase-1 deficiency, ornithine transcarbamylase deficiency, citrullinaemia type 1, argininosuccinic aciduria, hyperargininaemia, n-acetylglutamate synthase deficiency, ornithine translocase deficiency and lysinuric protein intolerance”.
Shire’s Xagrid
In the post-authorization setting, the CHMP is considering a proposal from Shire to switch the marketing authorization (MA) under exceptional circumstances for its thrombocythemia treatment, Xagrid (anagrelide), to a standard MA. Xagrid was approved in 2004. It was originally designated an orphan medicine in December 2000; it was withdrawn from the EU register of orphan products in November 2016 at the end of the 12-year period of market exclusivity.
Also in the post-authorization setting, sixteen indication extension requests are being considered for products that are already on the market.
The EMA will issue the meeting highlights on April 27.
From the editors of Scrip Regulatory Affairs.