#118 – Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging

KEYPOINTS

• 01

  Context: the phase 3 trial later failed

  This interview was recorded in September 2019. Attia notes up front that resTORbio's phase 3 trial of RTB101, discussed throughout, was later published and did not meet its primary endpoint. Everything said about that programme should be read with that in mind. Lloyd Klickstein, a rheumatologist and immunologist, left Harvard academia in 2006 for the Novartis Institutes, partly because grant funding had become far more competitive than in the late 70s and early 80s.

• 02

  Translational medicine works in both directions

  At Novartis, Klickstein set up a 'new indication discovery unit' around 2008–09. It chose projects with real medical need, scientific tractability, and no existing Novartis work (ideally no one else's either). Joan Mannick brought the idea of testing mTOR inhibition against ageing of the immune system and started the project around 2010. Klickstein stresses that observations can move from humans back to animals as well as forward.

• 03

  The 2009 mouse study made rapamycin a credible longevity drug

  Rapamycin extended lifespan in mice that were already about 600 days old, an age at which caloric restriction no longer extends life. Klickstein cites gains of roughly 15% and 25%. TOR was identified in yeast by Michael Hall's work in 1991 and in mammals in 1994, including by Sabatini. Ilya Mechnikov's work on cells that engulf pathogens (phagocytosis) earned a share of the 1908 Nobel Prize.

• 04

  mTORC1 and mTORC2 behave differently

  Rapamycin, bound to FKBP12, inhibits mTORC1 but acts unevenly on its targets, more weakly on 4E-BP1 and less still on ULK1, which helps start autophagy. It doesn't directly inhibit mTORC2. With sustained exposure, though, signs of mTORC2 inhibition appear within a week to a month: high blood sugar and high triglycerides. Klickstein says the exact mechanism isn't known.

• 05

  Dose and schedule determine whether it boosts or suppresses immunity

  The 2014 trial gave adults over 65 the rapalog everolimus (RAD001) in one of three regimens. 0.5 mg daily gave partial, sustained mTORC1 inhibition. 5 mg weekly gave full inhibition for a couple of days. 20 mg weekly fully inhibited it throughout. High doses of rapalogs are immunosuppressive, which is why rapamycin (sirolimus, approved in 1999) is used in transplant patients.

• 06

  The 2014 result: a better flu-vaccine response at low doses

  The pre-specified target was a 1.2-fold improvement in flu vaccine response for two of three strains, the threshold earlier work linked to fewer symptomatic infections. Both low doses reached it, but 20 mg weekly improved only one strain. Checkpoint proteins such as PD-1, markers of exhausted T cells, fell by about 10–20% on CD4 and CD8 T cells. Adverse events also listed fewer infections over the following year, although influenza alone was too rare to analyse.

• 07

  Side effects rose with dose

  Attia remembers mouth ulcers as the classic side effect in transplant patients on 2–4 mg daily. In the trial, mouth ulcers affected about 4% of people on 0.5 mg daily or 5 mg weekly, compared with about 17% on 20 mg weekly. Total adverse events rose with dose, from about 35 to 46 to 109 across the three drug arms of roughly 53 people each. That supports the idea of a therapeutic window for low or intermittent dosing.

• 08

  The 2018 study added a catalytic inhibitor

  In 264 older adults, BEZ235 (later RTB101), an inhibitor that blocks mTOR's catalytic site, and its combination with RAD001 reduced respiratory tract infections. The combination and RAD001 improved flu vaccine response, but RTB101 alone did not. Klickstein clarified that RTB101 is not everolimus combined with something else.

• 09

  The phase 2b refined the target population

  With 652 patients across southern- and northern-hemisphere cold and flu seasons, 10 mg of RTB101 once daily again reduced respiratory infections. Benefits were seen in people over 85 and those with asthma or diabetes, but not in smokers or people with COPD. It was used to power phase 3, which included a fully enrolled study of 1,024 people aged 65 and over treated for 16 weeks.

• 10

  Fasting and rapalogs overlap but aren't the same

  Klickstein mentions a mouse study in which 24 hours of fasting before an otherwise lethal ischaemia–reperfusion injury let most or all of the mice survive, while fed mice died. He doesn't know how to extrapolate that to humans, since the metabolic consequences of the fast may matter more than its length.