After Jefferies analyst Peter Welford said in a late August report that Puretech Health plc affiliate Restorbio Inc. was "fast grabbing our attention," investors are paying heed as well, helping the company to a $40 million series B round to advance the immunotherapy RTB-101, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, through its phase IIb study and potentially into phase III for reducing the incidence of respiratory tract infections (RTIs) in elderly people.

RTB-101 is undergoing tests alone and with Afinitor (everolimus), an approved mechanistic target of rapamycin (mTOR) inhibitor, through an agreement with owner Novartis AG. Restorbio said the funds are also expected to pay for expanding the RTB-101 program into a phase II experiment in another aging-related indication. The round was led by Orbimed and included participation from Fidelity Management & Research Co., Rock Springs Capital, Quan Capital and Nest Bio. Restorbio has raised $65 million this year, including a $25 million series A financing.

Just last week, an independent data monitoring committee unanimously recommended moving the RTB-101 phase IIb study into its second portion. The effort is a dose-range finding study of the orally given therapy and is designed to assess the safety, tolerability and efficacy of 16 weeks of treatment standing alone or paired with Afinitor.

Although, as gerontologists like to remind people, aging is not a disease, it's the primary risk factor for most chronic illnesses, including cancer, heart disease, neurodegenerative trouble and diabetes. The costs are personal and economic, and the World Health Organization estimates that between 2015 and 2050, the world's population of people over age 60 will nearly double from 900 million to 2 billion, or 12-22 percent of the world's population.

In March, Puretech entered the deal with Basel, Switzerland-based Novartis to advance a pair of programs that take aim at mTORC1 under Restorbio's aegis, with the first focus in immunosenescence, the gradual loss of immune protection that underlies RTIs in the elderly. Under the terms of the agreement, Restorbio took an exclusive license to the two programs, with Novartis getting equity in Restorbio plus eligibility for milestone payments, as well as royalties if all goes well. Puretech said it had allocated about $15 million in several tranches to the research push as it progresses and continues to be de-risked, which would mean ownership of about 58 percent of the company on a diluted basis. As time goes on, Puretech's ownership could rise to about 67 percent through the allocation of $10 million more, the company said.

Trying RTB-101 with Afinitor makes perfect sense, as mTOR is a protein serine/threonine kinase that regulates multiple cell functions, including cell growth and metabolism, via TORC1 and TORC2. Blocking TORC1 seems to lessen the bad effects of aging, although knocking out TORC2 has been associated with adverse events, including hyperglycemia and hypercholesterolemia.

Restorbio and Novartis are not the only players in mTORC1. Last month, Cambridge, Mass.-based Navitor Pharmaceuticals Inc. designated its direct mTORC1 activator small-molecule NV-5138 as the company's lead candidate for treatment-resistant depression (TRD). The disclosure came as the firm laid out what it called "groundbreaking" data with NV-5138 in preclinical studies, including several models of depressive-like behavior, at the Society for Neuroscience annual meeting in Washington.

Ketamine uncontravened?

Navitor also made known its drug development strategy of targeting nutrient sensor proteins, which enabled the identification of NV-5138, a small molecule targeting Sestrin2 to selectively modulate mTORC1 signaling in neurons to intervene in the disease process underlying TRD. The company's preclinical findings show mTORC1 activation is critical for the efficacy of rapid-acting modulators of the N-methyl-D-aspartic acid (NMDA)-mediated signaling pathway such as ketamine.

Ketamine research in depression is hot. At the start of the year, New Brunswick, N.J.-based Johnson & Johnson (J&J) said its Janssen Pharmaceuticals unit entered a deal with Amorsa Therapeutics Inc., of Southborough, Mass., to develop and commercialize a small-molecule therapy for TRD based on the latter's ketamine analogue technology. Janssen took a worldwide exclusive option to license one of the preclinical drug candidates and agreed to shoulder the clinical, regulatory and commercial development burdens of going farther, should it succeed. Amorsa got an up-front payment of undisclosed value along with research funding, and is eligible to receive preclinical, clinical, regulatory and sales milestones, plus tiered royalties on product sales. The deal added another would-be jewel to J&J's existing ketamine program, under which it's developing the NMDA receptor antagonist esketamine for the treatment of major depressive disorder with imminent risk for suicide. (See BioWorld Today, Jan. 6, 2017.)

Esketamine might ring a bell. In the summer of 2016, Zug, Switzerland-based Auris Medical AG's shares took a pounding on news that its lead drug, Keyzilen (AM-101, esketamine hydrochloride gel), failed the first of two phase III trials in acute inner ear tinnitus.

Called TACTT2, the trial assigned 343 patients with a recent, documented experience of either traumatic cochlear injury or middle ear infection (otitis media) to a drug treatment arm or a placebo arm. The randomization was performed in a 3-to-2 ratio. The analysis was conducted on a modified intent-to-treat population of 326 patients. Keyzilen failed to show any difference from placebo with respect to two co-primary endpoints: an improvement in tinnitus loudness from baseline to day 84 and an improvement in tinnitus burden over the same time frame, as measured using the Tinnitus Functional Index. Data from the second phase III experiment are due in the first quarter of next year. (See BioWorld Today, Aug. 19, 2016.)

Also last year, Nature published findings that showed ketamine's antidepressant actions may be mediated by one of its metabolites. (2R,6R)-hydroxynorketamine, or HNK, does not appear to have the psychoactive side effects that are part of what keeps ketamine from being more widely used as an antidepressant. Ketamine works, but it's also a street drug, with high abuse potential, and it has side effects that include dissociation. (See BioWorld Today, May 5, 2016.)

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