It may seem surprising, but Achaogen is developing a new aminogycoside for the treatment of multi-drug resistant bacteria, including carbopenem resistant bacteria. Achaogen filed an NDA in Oct 2017. In May, an FDA Advisory Committee voted 15-0 to recommend approval of plazomicin for the treatment of complicated UTI, but voted against recommending approval of the drug for bacteremia (4-11 to approve).
Achaogen announced that plazomicin was found to be non-inferior to meropenem for complicated UTI in a 609 patient, Phase III, EPIC trial. The drug also demonstrated lower mortality and complication rate than colestin in Phase III, CARE trial that enrolled 69 patients with carbapenem-resistant enterobacteriaceae bacteremia that were receiving meropenem or tigecycline. The original study was to include a cohort of patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP), but due to problems in recruiting patients, the bacteremia cohort was combined with the HABP/VABP. With the lower patient population, no statistical analysis was possible.
Current trial data display no significant safety concerns; no independent safety data are yet available. The most common ADR reported in trials are diarrhea, hypertension, headache, nausea, and vomiting. In a review the FDA concluded that transient nephrotoxicity was seen in trials. While the sample size of the bacteremia trial was too small to determine if there was less nephrotoxicity than colistin, there was a trend in that direction. There was no ototoxicity found in studies, but the FDA did not feel the evidence of definitive.
Researchers at Hartford Hospital, examined the compatibility of plazomicin with 92 drugs in a simulated Y-site administration test. Plazomicin was compatible with 79 of the drugs (31 antibiotics) and incompatible with 13.
Plazomicin has a PDUFA date of June 25, so we will likely see the first new aminoglycoside in decades be approved.
Calcitonin gene–related peptide (CGRP) is a neuropeptide that has both cerebral arteriolar dilating and pain modulation properties. Decreasing CGRP is thought to increase inhibitory mechanisms which decreases the occurrence of migraine headaches. Four monoclonal antibodies are being developed for migraine prophylaxis.
Erenumab is a monoclonal antibody that inhibits the calcitonin gene–related peptide (CGRP) receptor. The drug is administered as a subcutaneous injection once a month. Erenumab decreased monthly migraine days compared to placebo in three Phase III trials, Liberty, ARISE and STRIVE.The FDA approved erenumab for the prevention of migraines on May 17. The drug will have an annual WAC price of $6,900.
The other three monoclonal antibodies, eptinezumab, fremanezumab and galcanezumab, decrease migraine occurrence by binding directly to CGRP. I reviewed this class of drugs along with the small molecule CGRP receptor antagonist, atogepant, in the June 2017 issue of Hospital Pharmacy.
Galcanezumab reduced migraine days compared to placebo in the Phase II EVOLVE-1, EVOLVE-2 and REGAIN trials. Lilly recently announced that treatment with galcanezumab resulted in 8.7 fewer weekly headache attacks compared to 5.2 few attacks with placebo in patients with episodic cluster headaches. However, the drug did not reduce attacks in a chronic cluster headache trial. Lilly hopes to have FDA approval in the third quarter of the year to prevent migraines. Galcanezumab is also a monthly subcutaneous injection.
In two Phase III trials, HALO-EM and HALO-CM, fremanezumab reduced monthly migraine days compared to placebo with both a monthly and quarterly subcutaneous injection. In HALO-EM trial, treatment with fremanezumab resulted in 1.5 fewer migraine days compared to placebo in patients with episodic migraine. The HALO-CM trial involved patients with chronic migraine, where fremanezumab reduced the number of migraine days per month by 2 days compared to placebo. Fremanezumab had a June PDUFA date, but approval was delayed due to manufacturing issues at Celltrion, the contracted producer of the API. The new PDUFA date is 9/16/18.
Erenumab, fremanezumab and galcanezumab are all subcutaneous injectables. If Celltrion corrects its manufacturing issues, all three CGRP antibodies may be available before the end of 2018. Erenumab is available as a patient administered auto-injector. Lilly plans to offer an auto-injector for galcanezumab. Fremanezumab is a more viscous solution and will initially be offered as a prefilled syringe. So while the drug may be approved as a quarterly subcutaneous injection, it my require a visit to a physician's office for administration, while monthly doses of galcanezumab and erenumab can be administered by the patient. Teva is working on an auto-injection system for fremanezumab, but it is not known when it will be available.
The fourth drug is eptinezumab. In two Phase II trials (PROMISE-1 and PROMISE-2), eptinezumab reduced monthly migraine days compared to placebo. Eptinezumab is given as a quarterly intravenous infusion. Alder Pharmaceutical is expected to file a BLA in the second half of 2018 with possible approval in 2019.
Express Scripts is pushing CGRP inhibitor manufacturers to set a lower price for their drug, rather than set a high price and offer a rebate. Express Scripts also wants to set up performance contract for the drugs based on efficacy on use of the drug in their patients. ICER released an updated draft review of CGRP inhibitors on May 31, 2018. ICER found insufficient evidence to recommend erenumab or fremanezumab over oral preventative drugs or botulism toxin for prevention of migraine in untreated patients. ICER did find evidence of a benefit for use of erenumab or fremanezumab in patients that had previously failed preventative therapy for chronic migraine. Data was supportive but inconclusive for prevention of episodic migraine. ICER found insufficient evidence for use of galcabezumab in either indication. The drugs were found to be safe with the most common ADR of injection site reactions and upper respiratory symptoms. CGRP inhibitors were estimated to improve quality of life years (QALY) for episodic and chronic migraine patients. With an announced WAC price of $6,900/year for erenumab, ICER estimates an annual cost of $5,000/year after discounts. Erenumab or fremanezumab were found to be cost effective in QALY gained in patients that had failed at least one preventative therapy. The estimated cost per QALY were lower for chronic migraine compared to episodic migraine. The pharmaceutical industry-funded Institute for Patient Access criticized the initial draft of the report for focusing too much on QALY and calculations based on the payers perspective. With the announced price being below the place holder price used in the report, we may see revised calculations.
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