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Date: 2018-09-15

Type of information: Granting of a Market Authorisation in the US

Product name: Ajovy ® (fremanezumab -TEV-48125 -formerly LBR-101/ RN-307)

Compound: fremanezumab

Therapeutic area: CNS diseases - Neurological diseases

Action mechanism:

  • monoclonal antibody. TEV -48125 (formerly LBR-101/ RN-307) is a monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), a well-validated target in migraine. CGRP signaling may be disrupted by targeting the ligand itself or its receptor. Teva's approach targets the ligand, allowing for some CGRP signaling during therapy, which may avoid the potential, unknown, effects of a long-term total disruption to the normal physiological functions of the CGRP system.
  • TEV-48125 is being developed for two distinct migraine indications; chronic migraine and high frequency episodic migraine. Positive results from the Phase IIb chronic migraine study were announced in February 2015 , demonstrating a significant reduction in both the number of monthly cumulative headache hours, and the number of headache days of at least moderate severity, relative to baseline, and for the first time validating the target in chronic migraine.
  • TEV-48125 successfully completed five Phase I trials with 94 healthy volunteers. Results were published in Cephalalgia, the official journal of the International Headache Society , in December 2013 , and presented at the 2014 annual meeting of the American Academy of Neurology .

Company: Teva Pharmaceuticals (Israel)

Disease: migraine

Latest news:

  • • On September 15, 2018, the FDA approved Ajovy ® (fremanezumab-vfrm) for the preventive treatment of migraine in adults. Ajovy® is the second FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide (CGRP), a molecule that is involved in migraine attacks. Aimovig® (erenumab-aooe), the first in this class, was approved on May 17, 2018.
  • Ajovy® is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients. Hypersensitivity reactions, including rash, pruritis (itching), drug hypersensitivity, and urticaria (hives) were reported with Ajovy in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required corticosteroid treatment. Most reactions were reported from within hours to one month after administration. The most common adverse reactions were injection site reactions and infections.
  • Ajovy® was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (=5 percent and greater than placebo) were injection site reactions.
  • Ajovy® is available as a 225 mg/1.5mL single dose injection in a prefilled syringe with two dosing options - 225 mg monthly administered as one subcutaneous injection, or 675 mg every three months (quarterly), administered as three subcutaneous injections. It can be administered in office by a healthcare professional or at home by a patient or caregiver. No starting dose is required to begin treatment.
  • The U.S. Wholesale Acquisition Cost (WAC) of Ajovy® is $575 per monthly dose and $1,725 per quarterly dose. Ajovy® will be available through retail and specialty pharmacies in approximately two weeks. There is a savings offer for Ajovy®. Commercially insured patients may pay as little as $0 on prescriptions for Ajovy® until the offer expires. Teva Shared Solutions® is available to provide support services for patients and offices.
  • • On December 18, 2017,  Teva Pharmaceutical Industries  announced the FDA has accepted for review the company's Biologics License Application (BLA) for fremanezumab, an anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibody for the preventive treatment of migraine. Additionally, the FDA has granted fast track designation for fremanezumab for the prevention of cluster headache. In order to bring this much-needed therapy to the migraine community, Teva acquired a priority review voucher to expedite the review of fremanezumab, which, if approved, would be a new preventive option for patients suffering from this debilitating disease. Regulatory action is anticipated by mid-2018.
  • The BLA includes data from the HALO clinical trial program, which enrolled more than 2,000 patients with episodic migraine (EM) and chronic migraine (CM), evaluating both quarterly and monthly dose regimens, in which fremanezumab achieved statistically significant results across all trial endpoints. Results of the HALO CM trial were recently published in The New England Journal of Medicine . The most common adverse events reported in clinical trials include injection transient and mild site induration, erythema, and itching at the injection site.
  • Fremanezumab is also being investigated for the prevention of chronic and episodic cluster headache as part of the Phase III ENFORCE clinical research program, which has been granted fast track designation by the FDA . Trial participant recruitment is now underway and the studies are expected to conclude in early 2019.
  • The Phase III HALO EM and CM studies were 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies to compare the safety, tolerability, and efficacy of four dose regimens of subcutaneous fremanezumab compared to placebo in adults with episodic and chronic migraine. The studies consisted of a screening visit, a 28-day run-in period, and a 12-week (84-day) treatment period, including a final evaluation at week 12 (end-of-treatment [EOT] visit, four weeks [28 days] after the final dose of study drug).
  • In the EM study, 875 patients were enrolled (294, 291, 290 patients in the placebo, quarterly, and monthly dose groups, respectively). Patients were randomized in a 1:1:1 ratio to receive subcutaneous injections of fremanezumab at 225 mg for three months (monthly dose regimen), fremanezumab at 675 mg at initiation followed by placebo for two months (quarterly dose regimen), or three monthly doses of matching placebo. The primary efficacy endpoint of the EM study was the mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the 12-week period after the first dose of fremanezumab.
  • In the CM study, 1,130 patients were randomized (around 376 patients per treatment group). Patients were randomized in a 1:1:1 ratio to receive subcutaneous injections of fremanezumab at 675 mg at initiation followed by monthly 225 mg for two months (monthly dose regimen), fremanezumab at 675 mg at initiation followed by placebo for two months (quarterly dose regimen), or three monthly doses of matching placebo. The primary efficacy endpoint of the CM study was the mean change from baseline (28-day run-in period) in the monthly average number of headache days of at least moderate severity during the 12-week period after the first dose of fremanezumab.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2018-09-15

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

  • • On July 3, 2018, the Institute for Clinical and Economic Review released a Final Evidence Report and Report-at-a-Glance on three calcitonin gene-related peptide (CGRP) inhibitors for prevention of migraine attacks: erenumab (Aimovig™, Amgen/Novartis), fremanezumab (Teva), and galcanezumab (Eli Lilly). ICER's report was reviewed at a June 2018 public meeting of the California Technology Assessment Forum (CTAF). Panel members voted that evidence was adequate to demonstrate a net health benefit of the CGRP inhibitors for individuals with chronic migraine and no other available treatment options. While acknowledging the significant impact even infrequent migraine has on day-to-day life, a majority of Panel members pointed to the unknown long-term risks in voting that current evidence is inadequate to show a net health benefit of the CGRP inhibitors for individuals with episodic migraine.
  • Panel members noted that the therapies may provide potential additional benefits beyond those studied in clinical trials, including reduced family/caregiver burden, a novel mechanism of action that may allow for successful treatment of patients without other options, and increased productivity. Further, the high severity and lifetime burden of illness, along with the significant uncertainty around long-term risks and the magnitude and durability of benefit, were noted as key contextual considerations that factored into CTAF's assessment of value.
  • Voting on the long-term value for money of erenumab, the only CGRP drug with a publicly-available price, a majority of the panel voted that erenumab represents an intermediate value in adults with chronic migraine, and votes were split between intermediate and low long-term value for money when the drug is used for patients with episodic migraine.
  • Following the voting session during the CTAF meeting, a policy roundtable of experts - including patient advocates, physicians, public and private payers, and drug manufacturers - convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:
  • When responsible pricing is accomplished and the net price of CGRP inhibitors aligns with the estimated added benefit for patients, prior authorization criteria should be relatively streamlined and allow documentation of eligibility through a clinician statement that patients have attempted adequate trials of two to three other preventive therapies rather than requiring extensive submission of clinical documents.
  • Following the example set by the launch of the first CGRP inhibitor, manufacturers should continue to exercise restraint and ensure net prices align reasonably with the added benefits for patients. Consideration of price increases in future years should be transparently justified by new clinical evidence of superior performance.Clinicians should be aware of the uncertainties in long-term efficacy and potential harms when prescribing CGRP inhibitors. The FDA has requested additional research into liver toxicity and risks for heart attack and stroke after exposure to erenumab, and into potential adverse effects when erenumab is used during pregnancy.

Is general: Yes