Welcome to your weekly digest of approaching regulatory and clinical readouts. Dova Pharmaceuticals could gain its first approval by May 21 when the FDA decides on avatrombopag, a thrombocytopenia project for chronic liver disease patients undergoing surgery. A green light would make this the first US-approved drug in this setting.
By midyear Glaxosmithkline is due to report phase III data on its latest HIV doublet, dolutegravir plus lamivudine. The studies are in treatment-naive patients, and the combination is a valuable part of the company’s HIV franchise. However, resistance was seen in a previous trial, and any repeat of this will be scrutinised.
A first for Dova
Avatrombopag is a second-generation thrombopoietin receptor agonist (TPO-RA) that aims to increase platelet counts in chronic liver disease patients with thrombocytopenia undergoing elective surgery. Platelet transfusions are the current standard of care to reduce the risk of bleeding during invasive procedures, but can carry a risk of transfusion reactions and infections.
Dova estimates that 70,000-210,000 procedures are scheduled in this population each year. The filing for avatrombopag, an oral treatment, was based on two double-blind, placebo-controlled phase III trials, Adapt-1 and Adapt-2.
In total 435 adults were recruited, and in each trial the population was split into two cohorts according to mean baseline platelet count. The lower count group were given 60mg avatrombopag once daily for five days and the higher count group received 40mg. Both cohorts had a placebo comparator. After the five-day treatment there was a five-day wait with a platelet check before surgery.
Both studies met the primary endpoint of the proportion of patients not requiring platelet transfusion or any bleeding rescue procedure up to seven days post-procedure, versus placebo. Avatrombopag also beat placebo on both secondary measures – patients achieving target platelet count on procedure day, and magnitude of change in platelet count from baseline to procedure day. The safety profiles of treatment and placebo were similar.
Avatrombopag sales are forecast to reach $525m by 2024, according to sellside consensus from EvaluatePharma. Dova went public with a $75m IPO last year, and shares are up 26% to date.
The lead competitor for Dova is Shionogi’s lusutrombopag, which has a PDUFA date in August for a similar patient population. This TPO-RA is approved in Japan as Mulpleta. Bearing in mind the imperfections of cross-trial comparisons, Dova’s asset seems to have greater efficacy than lusutrombopag, and the latter also needs up to seven days’ dosing versus avatrombopag’s five.
Leerink analysts are modelling a 40/60 market split by 2021 for lusutrombopag and avatrombopag respectively.
|Adapt-1 (study 310)||NCT01972529|
|Adapt-2 (study 311)||NCT01976104|
Twin test for Glaxo
Meanwhile, Glaxo is soon to report data from two phase III trials testing its dolutegravir and lamivudine doublet in HIV. The Gemini 1 and 2 studies each enrolled over 700 treatment-naive subjects, and tested the doublet against a three-drug regimen of dolutegravir plus Truvada (tenofovir/emtricitabine), both given one daily, aiming to demonstrate non-inferiority.
The primary efficacy endpoint, the percentage of subjects with plasma HIV 1 RNA of <50 copies/ml, will be measured at 48 weeks, and the trials will form the basis of a US submission later in the year.
Investors will be looking for any hint of resistance after a case was seen last year in a small investigator-led study. Glaxo played this down, blaming it on a “chaotically non-adherent” patient, but poorly compliant patients represent the real-world population (Glaxo runs into double trouble in HIV, July 27, 2017).
Glaxo already has an approved doublet, Juluca, a combination of dolutegravir and rilpivirine. Juluca treats well-controlled patients switching from a triplet regimen, a smaller population than dolutegravir and lamivudine’s intended treatment-naive group.
Forecasts for the dolutegravir/lamivudine doublet sit at $907m by 2024, according to EvaluatePharma, making it Glaxo’s third-most valuable HIV product. The group will have to deliver a clean safety profile in the ongoing phase III trials if it wants to keep up with expectations.
|Glaxo's biggest-selling HIV drugs by 2024|
|Global sales ($m)|
|Triumeq||Abacavir + dolutegravir + lamivudine||3,845||4,281||4,503||4,731||Marketed|
|Dolutegravir & lamivudine||Dolutegravir + lamivudine||-||233||607||907||Phase III
|Cabotegravir & rilpivirine||Cabotegravir + rilpivirine||-||116||382||644||Phase III|
|Juluca||Dolutegravir + rilpivirine||89||252||358||457||Marketed|