7 replies to this topic

[Michael]

All:
 
A followup to the earlier Mannick et al open-label pilot study with everolimus, which only showed improved flu vaccine response:
 

TORC1 inhibition enhances immune function and reduces infections in the elderly
By Joan B. Mannick, Melody Morris, Hans-Ulrich P. Hockey, Guglielmo Roma, Martin Beibel, Kenneth Kulmatycki, Mollie Watkins, Tea Shavlakadze, Weihua Zhou, Dean Quinn, David J. Glass, Lloyd B. Klickstein
Science Translational Medicine
11 Jul 2018: Vol. 10, Issue 449, eaaq1564
DOI: 10.1126/scitranslmed.aaq1564
 
The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks.
 
A low-dose combination of a catalytic (BEZ235 [=RTB101]) plus an allosteric (RAD001 [=everolimus]) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group.

 
 

[resTORbio Press Release]
 
In the RTB101 monotherapy and RTB101+everolimus combination treatment arms, statistically significant and clinically meaningful reductions in the annual rate of infections of 33% (p=0.008) and 38% (p=0.001), respectively, compared to placebo, were observed. In addition, both RTB101 monotherapy and the RTB101+everolimus combination therapy were observed to reduce the incidence of [respiratory tract infections (RTIs)] at one year by 42% (p=0.006) and 36% (p=0.01), respectively. [MR: It looks to me like combination therapy is a wash vs. everolimus alone]. The combination of RTB101+everolimus was also observed to significantly enhance the response to influenza vaccination and upregulated the expression of critical antiviral genes that play a key role in enabling the immune system to protect the elderly from respiratory tract infections.
 
RTIs are the fourth leading cause of hospitalizations and the seventh leading cause of death in people aged 65 years and older in the United States. Moreover, the majority of RTIs in the elderly are caused by viruses for which there are currently no approved therapies. resTORbio’s TORC1 inhibitor program has the potential, if successfully developed and approved, to be a new class of immunotherapy that enhances the function of the aging immune system to fight infectious pathogens including viruses, and thereby reduce the incidence of respiratory tract infections.
             
Based on the results of the Phase 2a study, resTORbio is conducting a Phase 2b clinical trial to further investigate the potential benefits of RTB101 alone and in combination with everolimus in aging-related diseases. In the ongoing Phase 2b study, doses of RTB101 alone and in combination with everolimus are being evaluated as an immunotherapy to decrease the incidence of RTIs in older people at increased risk of morbidity and mortality from RTIs (defined as age 85 and older and age 65 and older with comorbidities). Dosing has been completed in the Phase 2b study and 16-week topline data are expected to be reported in the third quarter of 2018.

 

Possible Anti-Aging Drugs Boost Elderly Immune Systems
... After a year, the study subjects who got the two-drug combination reported 1.49 infections, such as colds and bronchitis, the researchers report. Those who took the placebo reported 2.41 infections. That works out to be about a 40 percent reduction.
 
"That's a big reduction," Mannick says. [MR: on a relative basis, yes — but it's a small absolute effect in a small number of subjects in each arm].

The drugs also boosted how the elderly study subjects' immune systems responded to a flu vaccine — increasing the levels of flu antibodies their immune systems produced by more than 20 percent, Mannick says. ...
 
The researchers stress that more research is needed to confirm the findings and show the drugs are safe. And at least one researcher says the findings are based on a relatively small number of people and used methods that could produce misleading results. [The article never clarifies what these methods are -MR]
 
Still, many researchers say the findings are encouraging.
 
"I think the results are quite exciting," says Felipe Sierra, director of the division of aging biology at the National Institute on Aging. ... "It is possible that further research with this same combination of drugs or similar combinations will lead to a possibility of addressing multiple chronic diseases because these drugs have been shown to affect the process of aging itself," Sierra says. ...

"It is premature, in my opinion, to rule out major negative effects of the pharmacological agents used in this study among sub-sets of human subjects," wrote George Martin, a professor emeritus of pathology at the University of Washington. ...

Aubrey de Grey, an aging researcher at the SENS Research Foundation in Mountain View, Calif., says that "perhaps the most exciting aspect of the results is that the protection lasted for the duration of the study, namely a year, even though the drug was only given for the first six weeks."

Effects of Everolimus and RTB101/BEZ235 on mTOR Signaling. From resTORbio Website

 

About RTB101 [resTORbio Website]
RTB101 is an orally administered, small molecule, potent TORC1 inhibitor. RTB101 partially inhibits TORC1 by binding to the active site of mTOR on the TORC1 complex, a mechanism known as catalytic inhibition. [That sounds like classic competitive inhibition to me, but I'm coming at this from no deep reading —MR]. ... Everolimus partially inhibits TORC1 by changing the shape of TORC1, a mechanism known as allosteric inhibition.  The combination of RTB101 and everolimus may yield complete and selective TORC1 inhibition.

 

NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G₁ arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. ...
 
NVP-BEZ235 significantly reduced the phosphorylation levels of the mTOR activated kinase p70^S6K (Fig. 3A). This kinase is activated by the TORC1 complex, which itself is relieved from a negative regulation by the TSC1/2 complex in a PI3K- and Akt-dependent manner (35). Cell line lacking functional TSC complexes (TSC1-null MEF) are characterized by a constitutively active mTORC1 complex (36). As expected, TSC1-null MEF exposed RAD001 showed a complete reduction of S235/S236P-RPS6 levels, even at the lowest concentration tested (1 nmol/L). Under similar experimental conditions, NVP-BEZ235 also led to a reduction of S235/S236P-RPS6 levels with an IC₅₀ of 6.5 nmol/L (Fig. 3C), suggesting that NVP-BEZ235 can directly inhibit the mTOR kinase, as the kinase domain of mTOR is highly homologous to the one of class IA PI3K. The activity of NVP-BEZ235 against mTOR was confirmed using a biochemical mTOR K-LISA assay (IC₅₀, 20.7 nmol/L; Supplementary Fig. S4A).⁶ To test whether NVP-BEZ235 inhibits both mTORC1 and mTORC2 complexes, immunokinase assays were done using 4E-BP1 (Phas) as a substrate. Maximum activity of TAP-tagged immunoprecipitated Raptor (mTORC1) or Rictor (mTORC2) kinase complexes was reached after an incubation period of 30 min (Supplementary Fig. S4B).⁶ The addition of NVP-BEZ235 to otherwise similar assay conditions caused a concentration-dependent decrease in mTORC1 and mTORC2 activities (Fig. 3D). Altogether, these data show that NVP-BEZ235 is also a mTORC1/2 catalytic inhibitor.
 
PMID 18606717

[VP.]

What is "RTB101" ?  Is it a rapalog?

Edited by VP., 12 July 2018 - 02:14 AM.

[albedo]

Encouraging news, thank you Michael for sharing them on this Board.

[VP.]

Is the company trying show that it's proprietary drug RTB101 is better than Everolimus (a rapalog with a shorter half life). I'm not sure this study shows that. As Micheal points out the combo is a wash and Everolimus was not tested by itself as a control. Is that why the stock price action is so muted? Everolimus will be off patent by the time all the studies are done and I have my doubts that the combo is necessary for the results. I can't look at the study from work but if someone has access please comment. 

[albedo]

I thought useful to share here an indirectly related article by the same team (Mannick et al) on the positive impact on kidney function. IMHO, I found not hugely surprising that the effect is more pronounced on kidneys which lack the powerful regenerative power of liver. Also, kidney function, e.g. as measured by the decline of eGFR, is a clear indicator of aging. Moreover the c-Myc regulation is interesting as it is one of the 4 Yamanaka's factors (the "M" of OSMK) whose induction seems leading to reversal of the hallmarks of aging on the cellular road to pluripotency (iPSC).

 

Shavlakadze T, Zhu J, Wang S, et al. Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology. J Gerontol A Biol Sci Med Sci. 2018;73(7):845-852.

 

"Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes."

[QuestforLife]

But isn't c-Myc activated during epigenetic de differentiation, which is the opposite of the effect of MTOR inhibitors, which will reduce it?

It is likely excessive mTOR activation is harming the kidney in old age, and c-Myc is downstream of that, and this being curtailed is providing beneift.

I could be wrong of course, so feel free to propose other mechanisms.

[albedo]

But isn't c-Myc activated during epigenetic de differentiation, which is the opposite of the effect of MTOR inhibitors, which will reduce it?

It is likely excessive mTOR activation is harming the kidney in old age, and c-Myc is downstream of that, and this being curtailed is providing beneift.

I could be wrong of course, so feel free to propose other mechanisms.

 

Yes, I noticed that too. I am not fully sure and need to read more but the text seems to me pointing in the direction you emphasize:

 

"...One gene-set that was upregulated in rat kidney when comparing 6- to 24-month-old animals was c-Myc target genes (Figure 2). This finding was confirmed by examining specific genes in the pathway by RT-qPCR (Figure 5A). In the kidney, c-Myc mRNA itself was upregulated with age, and counter-regulated by 6-week treatment with the rapalog, as were genes that fall under the Myc-regulated pathway. This was of particular interest for a couple of reasons: first, it was recently shown that Myc haplo-insufficient mice had prolonged lifespans, and demonstrated a downregulation of several pathways, including mTORC1 signaling (17). A distinct study very recently demonstrated that transient upregulation of the Yamanaka factors, the four genes which are required to epigentically reprogram cells to their dedifferentiated form, inducing the formation of induced-pluripotent cells, could significantly increase life span (28). One of those genes is c-Myc (28). The combination of these studies and our current work point to a key role Myc may be playing in regulating the epigenetic changes associated with aging, and the potential therapeutic value of inhibiting those Myc-induced changes to treat age-related diseases, also highlighting mTORC1 inhibition as a strategy to intervene when Myc or Myc-induced genes are elevated. Of course, it is also of interest to note that part of the mechanism by which mTORC1 inhibition perturbs aging might be its ability to inhibit Myc, and this is a mechanism not previously implicated for rapalogs...." (emphasis mine)
 

[QuestforLife]

I'm guessing here, but c-myc is a growth factor and it's involved in spurring regeneration of tissue. But in an exhausted tissue (no stem cells, short telomeres in somatic tissue) it does more harm than good. Hence rapalogs blocking senescence.