In long-anticipated draft guidance on interchangeability of biosimilars, FDA said it will require most biosimilars' sponsors to conduct studies showing that switching between a biosimilar and its reference product poses no greater risk than continuing to use the reference product. The guidance recommended designs for switching studies, as well as integrated trials to show that a compound is both biosimilar to and interchangeable with its reference biologic.
The agency said it will "generally" require switching studies to show interchangeability between any biological products that are dosed more than once. Switching studies should evaluate pharmacokinetic and pharmacodynamic measures as primary endpoints, while also assessing immunogenicity and safety. The agency specified that the studies should include at least three switches between a reference product and proposed biosimilar; the last switch should be a transition to the proposed biosimilar from its reference product.
FDA emphasized that an imbalance in adverse events or immune responses reported at any point during a switching study will "raise concerns" as to the biologics' interchangeability, because it may be difficult to determine which product caused the event. The agency also encouraged powering studies to accommodate patient dropouts, noting that an imbalance in dropout rates may also suggest that compounds are not interchangeable.
The agency encouraged companies to first seek a candidate's approval as a non-interchangeable biosimilar if there is "residual uncertainty regarding interchangeability" based on adverse events. The sponsor could then conduct postmarketing studies to show interchangeability.
FDA suggested a two-part study design for sponsors seeking evidence of both biosimilarity and interchangeability. The agency said that after an appropriate measure of clinically meaningful differences between two biologics, a second stage of an integrated study could re-randomize patients into a switching study. The study should be powered to adequately measure both PK and PD, as well as clinical effectiveness.
The guidance said sponsors seeking to extrapolate data supporting interchangeability to additional indications "need to provide sufficient scientific justification" that addresses factors such as immunogenicity risk, PK and mechanism of action.
FDA will accept comments on the draft guidance through March 19. In a Federal Register notice accompanying the guidance, FDA asked stakeholders to address how the agency should consider additional indications approved for a reference product after approval of its interchangeable product, and if the agency should change or add to its comparability assessments for post-approval manufacturing changes of interchangeable products.
Forward Pharma A/S (NASDAQ:FWP) gained $8.85 (48%) to $27.20 after it said it will receive $1.25 billion from Biogen Inc. (NASDAQ:BIIB) as part of a licensing and settlement agreement related to the companies' patent dispute. Biogen said the deal will "clarify and strengthen" its IP protection for multiple sclerosis drug Tecfidera dimethyl fumarate.
The deal does not resolve existing patent litigation between the companies concerning use of a dimethyl fumarate formulation to treat MS. Forward said it will grant Biogen co-exclusive U.S. rights, and exclusive worldwide rights, to IP related to dimethyl fumarate. If certain legal conditions are met, the U.S. rights may convert to an exclusive license.
If Forward wins an ongoing interference proceeding with the U.S. Patent and Trademark Office, it will be eligible for 10-20% royalties on Tecfidera sales, beginning in 2021, under the exclusive license. If the license remains co-exclusive and Forward retains rights to the relevant IP, the royalty would be 1% beginning in 2023.
If Forward prevails in a separate opposition proceeding with the European Patent Office, it would also be eligible for 10-20% royalties on Tecfidera sales outside the U.S.
Both patent cases address use of 480 mg of dimethyl fumarate to treat MS (see BioCentury Extra, March 10, 2016).
Forward said it is evaluating the most efficient way to deliver "a substantial portion" of the Biogen payment to shareholders, and is considering stock buybacks and cash distributions. The agreement is subject to Forward shareholders' approval at a Feb. 1 meeting.
Biogen shed $1.64 to $283.11 on Tuesday.
AstraZeneca plc (LSE:AZN; NYSE:AZN) updated its analysis plan for its Phase III MYSTIC trial of durvalumab (MEDI4736) and tremelimumab (CP-675) as first-line therapy for non-small cell lung cancer (NSCLC). The trial's primary endpoints will now include overall survival (OS) for durvalumab monotherapy, as well as existing primary endpoints evaluating OS and progression-free survival (PFS) for the combination.
AZ now expects PFS data in mid-2017 and OS data next year "at the latest." It had previously guided for PFS data in 1H17.
MYSTIC is evaluating durvalumab monotherapy only in PD-L1-positive patients. It is studying the combo's effects on PFS and OS in "all comers." Durvalumab is a mAb targeting PD-L1, while tremelimumab targets cytotoxic T-lymphocyte associated protein 4 (CTLA4; CD152).
Buysiders are watching MYSTIC closely as the first-line NSCLC market develops. Opdivo nivolumab from Bristol-Myers Squibb Co. (NYSE:BMY) missed the primary endpoint of a first-line NSCLC trial last year, while Keytruda pembrolizumab from Merck & Co. Inc. (NYSE:MRK) is under Priority Review from FDA in an NSCLC indication broader than that for which it is already approved (see BioCentury, Jan. 2 and BioCentury Extra, Jan. 11).
Also on Tuesday, AZ said it will expand a separate Phase III study of the combo to obtain localized data for use in regulatory applications in China. It expects OS data next year from that trial, NEPTUNE, in first-line NSCLC.
Allergan plc (NYSE:AGN) and Gedeon Richter Ltd. (Budapest:RICHTER) said ulipristal acetate (PGL4001) met all co-primary and secondary endpoints in VENUS II, the second of two Phase III trials evaluating the compound to treat uterine fibroids. The companies expect to submit an NDA to FDA in 2H17 for the selective progesterone receptor modulator (SPRM).
Compared to placebo, the study's 5 mg and 10 mg doses of ulipristal significantly improved the percentage of patients with absence of uterine bleeding (42% for 5 mg and 54.8% for 10 mg ulipristal vs. zero for placebo), meeting a co-primary endpoint. Ulipristal also met a second co-primary endpoint, time to absence of uterine bleeding during the study's first 12-week treatment course.
The 432-patient study's secondary endpoints included percentage of patients without uterine bleeding from day 11 to the end of the first treatment course; percentage without bleeding after the second treatment course; time to absence of bleeding during course two; and change from baseline on a quality of life scale.
In May 2016, the partners said ulipristal met the co-primary and secondary endpoints of VENUS I, another Phase III study (see BioCentury Extra, May 9, 2016).
Gedeon has rights to ulipristal from HRA Pharma S.A. (Paris, France) to treat uterine fibroids, and markets the drug for the indication in the EU as Esmya. Allergan has rights in the U.S. and Canada under a 2010 deal, and markets it in Canada as Fibristal. It is also marketed as ella and ellaOne for use as an emergency contraceptive (see BioCentury Extra, Dec. 16, 2010).
Gedeon dipped HUF38 to HUF6,280 on Tuesday.
FDA issued draft guidance concerning medical product sponsors' communications, including promotional materials, that are "consistent with" products' labels, but not included in the labels. The guidance broadly recommended ways to convey "truthful and non-misleading" information that is consistent with a product's label, and compared specific examples of communications that "could be" consistent vs. those that would not be considered consistent.
For example, the guidance said information comparing two approved products for the same indication, providing context about adverse reactions, or discussing subgroups for which a product is approved could be consistent with labeling. The document says providing certain types of postmarketing data, including some patient reported outcomes, could also be consistent. Communications alone are not to be construed as evidence of a new intended use, the agency said.
The document said communications about use of a product in an indication or patient population for which it is not approved would fall outside the scope of what is considered consistent with its label, as would communications that conflict with required or recommended handling, use, dosing and administration. Any communications that could negatively affect a product's benefit-risk profile would not be considered consistent with the product's label.
The agency also outlined standards of evidentiary support for such communications, and recommended that companies seek medical, legal and regulatory advice prior to providing a communication about a product.
FDA approved Erelzi etanercept-szzs from Novartis AG (NYSE:NVS; SIX:NOVN) in August 2016; however, Novartis does not yet market the biosimilar in the U.S. The Jan. 9 BioCentury Extra misstated the biosimilar's marketing status.