In April 2015, Jacobus presented clinical trial results with 3,4-DAP at a scientific meeting.In December 2015 a group of 106 neuromuscular doctors who had worked with both Jacobus and BioMarin/Catalyst published an editorial in the journal, Muscle & Nerve, expressing concern about the potential for the price of the drug to be dramatically increased should Catalyst obtain FDA approval, and stating that 3,4-DAPP represented no real innovation and didnt deserve exclusivity under the Orphan Drug Act, which was meant to spur innovation to meet unmet needs. Catalyst responded to this editorial with a response in 2016 that explained that Catalyst was conducting a full range of clinical and non-clinical studies necessary to obtain approval in order to specifically address the unmet need among the estimated 1500-3000 LEMs patients since about 200 were receiving the product through compassionate use – and that this is exactly what the Orphan Drug Act was intended to do: deliver approved products to orphan drug populations so that all patients have full access.In December 2015, Catalyst submitted its new drug application to the FDA, and in February 2016 the FDA refused to accept it, on the basis that it wasnt complete. In April 2016 the FDA told Catalyst it would have to gather further data. Catalyst cut 30% of its workforce, mainly from the commercial team it was building to support an approved product, to save money to conduct the trials. In March 2018 the company re-submitted its NDA.
Lorlatinib, sold under the brand name Lorbrena in the United States, Canada, and Japan, and Lorviqua in the European Union, is an anti-cancer drug developed by Pfizer. It is an orally administered inhibitor of ALK and ROS1, two enzymes that play a role in the development of cancer. Medical uses
Lorlatinib is approved in the US and in Europe for the second- or third-line treatment of ALK-positive metastatic non-small-cell lung cancer (NSCLC). It is the only ALK inhibitor with meaningful activity against ALK G1202R mutation in lung cancer. Contraindications
Lorlatinib must not be combined with strong inducers (i.e. activators) of the liver enzymes CYP3A4/5 if it can be avoided, as serious cases of liver toxicity have been observed under combination with the CYP3A4/5 inducer rifampicin. Side effects
The most common side effects in studies were high blood cholesterol (84% of patients), high blood triglycerides (67%), edema (55%), peripheral neuropathy (48%), cognitive effects (29%), fatigue (28%), weight gain (26%), and mood effects (23%). Serious side effects led to dose reduction in 23% of patients and in termination of lorlatinib treatment in 3% of patients. Interactions
Lorlatinib is metabolized by the enzymes CYP3A4/5. Therefore, CYP3A4/5 inducers such as rifampicin, carbamazepine or St Johns wort decrease its concentrations in the blood plasma and can reduce its effectiveness. Additionally, the combination of lorlatinib with rifampicin showed liver toxicity in studies. Inhibitors of these enzymes such as ketoconazole or grapefruit juice increase lorlatinib plasma concentrations, leading to higher toxicity.