Welcome to your weekly digest of approaching regulatory and clinical readouts. Glaxosmithkline’s shingles vaccine will come before an FDA panel on September 13. Shingrix has shown impressive efficacy but comes with systemic side-effects, something the regulators will watch closely.
Also phase III data for Axovant’s 5-HT6 antagonist intepirdine in Alzheimer’s disease are due before the end of September. Alzheimer’s is of course a particularly risky area in which many projects have failed; this study will determine whether Axovant follows suit.
Valuable shingles vaccine
Shingrix is GSK’s sixth biggest growth driver with 2022 sales forecast to reach $1bn according to EvaluatePharma consensus. It has an NPV of $3.7bn, or 4% of the company’s market cap. Its biggest challenge will be wrenching market share from Merck’s Zostavax, which currently leads the space. Zostavax was approved in 2006 and last year sold $685m, but its US patent has now expired and sales are expected to fall (see table).
|Top selling shingles vaccines by 2022|
|Annual WW Sales|
|Zostavax||Merck & Co||685||703||592||548||Marketed|
|V212||Merck & Co||-||27||70||103||Phase III|
In a phase III trial called Zoe-50 Shingrix was given as two doses administered two months apart. Over 15,000 participants aged 50 and older were enrolled. Shingrix treatment resulted in a 97% reduction in risk of shingles after a mean 3.2 years follow up. There was no difference in efficacy across three age groups, including those over 70.
But the treatment had more adverse events than placebo, with 81.5% of the treated group experiencing injection site reactions versus 11.9% of the placebo arm, and 66.1% versus 29.5% on placebo had systemic reactions.
Shingrix’s high rate of injection site reactions could cause compliance issues for the second dose – Merck’s vaccine has an advantage here in that it is given as a single dose. However, Zostavax’s efficacy is said to decrease with age, with 69.8% efficacy between the ages of 50-59 years falling to 37.6% in those aged 70 and older, and its protection wanes within the first five years after vaccination. Also as a live attenuated vaccine Zostavax is contraindicated in immunocompromised people; Shingrix is a non-live vaccine.
Shingrix may have to contend with a limited patient pool because of vaccinations that have already occurred with Zostavax. To demonstrate re-vaccination efficacy GSK ran a trial called Zoster-048 that showed similar immune responses between patients who had received Zostavax at least five years prior to being vaccinated with Shingrix, and those without previous exposure to the Zostavax vaccine. The study was in 430 adults aged 65 and older.
The FDA adcom is taking place on September 13 and will no doubt focus on Shingrix’s safety. A final decision is due in October.
|Trial name||Trial ID|
Axovant’s big test
The phase III Mindset trial of Axovant’s intepirdine enrolled 1,315 patients with mild to moderate Alzheimer’s disease. Intepirdine, previously known as RVT-101, was given as a 35mg tablet once daily as an adjunctive treatment to 5mg or 10mg donepezil, versus placebo and donepezil.
The co-primary endpoints were change from baseline in cognitive subscale (ADAS-Cog-11) and activities of daily living (ADCS-ADL) at 24 weeks. A 12 month open-label study is ongoing.
Jefferies analysts give the Mindset trial a 50-60% probability of success. They state that a 1.5-point efficacy benefit in ADAS-cog will be seen as a successful result, whereas a statistically significant benefit of less than one point will be greeted less enthusiastically. That said, with few treatment options in this condition, even modest efficacy might be enough for approval.
Intepirdine has shown mixed results in phase II. As a monotherapy it failed but when used as an adjunct treatment to donepezil there was a statistically significant 1.5-point ADAS-cog benefit at 24 weeks. The co-primary endpoint in that trial was clinical dementia rating, a five-point scale of functional performance, and statistical significance was only evident at week 12. Therefore the trial failed to meet the overall criteria for success at 24 weeks.
However, on the secondary endpoint of ADCS-ADL there was a statistically significant improvement at 24 weeks, and this is now a co-primary endpoint in the phase III trial.
Most adverse events were of mild-to-moderate intensity, with headache, nasopharyngitis and diarrhoea among the top five most common.
Similar 5-HT6 antagonists have failed in late-stage trials mostly due to a lack of efficacy. Lundbeck’s idalopirdine was abandoned in phase III – a lower dose was tested as the 90mg used in phase II was linked with liver toxicity. Pfizer’s similar asset PF-05212377 was discontinued due to lack of efficacy, again suffering liver side effects at higher doses (Spotlight on Axovant after Lundbeck’s Alzheimer’s failure, September 23, 2016).
Axovant acquired worldwide rights to intepirdine from Glaxosmithkline back in 2014 for just $5m up front and has paid an additional $5m since. The agreement provides for a further $155m in milestone payments and a fixed royalty of 12.5%.
The bull thesis rests on Axovant finding the right therapeutic window, and 2022 forecasts sit at a substantial $1.7bn according to consensus from EvaluatePharma. The project’s NPV is $2.4bn, slightly more than the company’s market cap.
|Trial name||Trial ID|