CCL21

Very low risk for drug-drug interactions (DDI) with Mazindol ER based upon results from in vitro metabolism and transporter studies Demonstrated pharmacological differentiation versus currently available medications used to treat narcolepsy which can have significant DDI effects preventing co-administration or requiring dose adjustments ZURICH, SWITZERLAND / ACCESSWIRE / June 14, 2023 / NLS Pharmaceutics Ltd. (Nasdaq:NLSP, NLSPW) ("NLS" or the "Company"), a Swiss clinical-stage biopharmaceutical company focused on the discovery and development of innovative therapies for patients with rare and complex central nervous system disorders, today announced positive data from five recently completed in vitro drug-drug interaction studies investigating the potential for DDI of mazindol, a triple monoamine reuptake inhibitor and partial orexin-2 agonist, as well as its hydrolyzed metabolite (M6). Typical DDI studies include Cytochrome P450 (CYP), UDP glucuronosyltransferase (UGT) and transporter inhibition and induction studies to evaluate whether mazindol affects the pharmacokinetic (PK) effect of other drugs (mazindol as a "perpetrator"). In addition, in vitro studies are conducted with CYP and transporter substrates to evaluate whether other drugs can affect mazindol PK (mazindol as a "victim"). Following U.S. Food and Drug Administration (FDA) guidelines, the in vitro DDI studies were designed to evaluate the drug interaction potential across a wide range of metabolic enzymes and transporters when co-administered with mazindol. The mazindol in vitro studies examined the following: CYP Inhibition in Human Liver Microsomes CYP Induction in Cultured Human Hepatocytes CYP and UGT Reaction Phenotyping UGT Inhibition in Human Liver Microsomes ATP-binding case (ABC) and solute carrier (SLC) Transporter Inhibition and Substrate Potential in Cells and Vesicles Results of the in vitro perpetrator studies showed that mazindol and its hydrolysis metabolite do not have the potential to inhibit or induce the metabolism/transport of concomitant medications. Based on these in vitro data, it can be concluded that mazindol and the hydrolysis metabolite are not inhibitors of CYPs, UGTs, or transporters (including P-glycoprotein, breast cancer resistance protein [BCRP], organic anion transporter [OAT]1, OAT3 and organic cation transporter [OCT]2 and mazindol does not induce metabolism. Therefore, mazindol does not affect the PK of concomitant medications. Results of the in vitro victim studies showed that mazindol is not metabolized by CYPs or UGTs and is not transported by BCRP, OAT1, OAT3 and OCT2. Only the hydrolysis metabolite (but not mazindol) is a P-glycoprotein (Pgp) substrate; thus a clinical DDI study of mazindol is planned to quantify the potential for an increase in the hydrolyzed metabolite (M6) exposure in the presence of a Pgp inhibitor (e.g., Itraconazole). Otherwise, concomitant medications are not expected to affect the PK of mazindol. "We are pleased to have seen these positive results from our DDI in vitro study with mazindol, which further demonstrated its differentiated pharmacological and safety profile. This latest set of data reinforce that mazindol may have the potential to provide an advantage over other current treatments for patients with narcolepsy taking multiple drugs, including hormonal contraceptives, proton-pump inhibitors and anti-epileptic drugs, who are at higher risk of experiencing adverse drug interactions or even discontinuation of their medications due to those interactions," said George Apostol, MD, MS, Chief Medical Officer of NLS. "Based on these data, once-daily Mazindol ER shows potential to meet yet another unmet need of narcolepsy patients, in addition to its strong efficacy, fast onset of action, well demonstrated long-term safety profile, low scheduling and its unique mechanism of actions." Alex Zwyer, Chief Executive Officer added, "Discussions with both physicians as well as patient advocacy groups at SLEEP 2023, the annual meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS), held on June 3 - 7, 2023, in Indianapolis, reinforced the importance a mazindol's DDI drug pro realize an unmet need for patients." Beginning in July 2023, NLS will initiate the AMAZE development program for Mazindol ER, consisting of two pivotal Phase 3, randomized, double-blind, placebo-controlled, multicenter studies in the U.S. designed to assess the safety and efficacy of mazindol in patients with narcolepsy type 1 (NT1) compared to placebo. These two studies will enroll a total of 100 NT1 patients. Mazindol ER will be administered at fixed doses of 3 mg once daily for a total of eight weeks. A 52-week open-label extension will further evaluate the long-term safety and tolerability of Mazindol ER in NT1 patients. Topline data from the double-blind studies are expected in late 2024. About DDI in vitro studies DDI studies are a standard and necessary step required by the FDA and other regulatory agencies globally for approving a new drug to market. DDI studies help identify potential adverse reactions that may be caused by interactions between multiple drugs, leading to unintended reactions, toxic side effects, or in some cases, a lack of therapeutic efficacy. With the rise in polypharmacy to treat comorbidities, alongside prevalent substance abuse, drug-drug interactions have become a critical factor to consider when treating narcolepsy. Approximately 50% of prescribed drugs currently on the market are known to cause drug interactions with CYP3A4 inhibitors and can lead to side effects. Findings from DDI studies help to inform drug labeling that is then used by healthcare providers to aid in therapeutic decision-making. Currently available medications used to treat narcolepsy can have significant DDI effects which prevent co-administration or require dose adjustments of drugs like hormonal contraceptives, proton-pump inhibitors or anti-epileptic drugs. About Mazindol ER The Company's lead product candidate, Mazindol ER, is a proprietary extended-release formulation of mazindol and is being developed for the treatment of narcolepsy, and potentially other sleep-wake disorders such as Idiopathic Hypersomnia (IH), for which NLS recently obtained Orphan Disease Designation (ODD) from the FDA and the European Medicines Agency (EMA). Mazindol is a triple monoamine reuptake inhibitor and partial Orexin-2 Receptor agonist, which was used for many years to treat patients diagnosed with narcolepsy in compassionate use programs. A Phase 2 multi-center U.S. clinical study evaluating Mazindol ER in adult patients suffering from narcolepsy met its primary endpoint with high statistical significance and demonstrated a favorable safety and tolerability profile. NLS also successfully completed a Phase 2 study in the U.S. evaluating Mazindol ER in adult patients suffering from Attention Deficit/Hyperactivity Disorder (ADHD). The study met all primary and secondary endpoints and well-tolerated. Mazindol ER has received ODD both in the U.S. and in Europe for the treatment of narcolepsy. Up to 1/3 of narcoleptic patients are also diagnosed with ADHD. The Phase 3 program for Mazindol ER, AMAZE, will commence in July 2023. More information on these studies can be found at or . About NLS Pharmaceutics Ltd. NLS Pharmaceutics Ltd. (Nasdaq:NLSP) is a global development-stage biopharmaceutical company, working with a network of world-class partners and internationally recognized scientists, focused on the discovery and development of innovative therapies for patients with rare and complex central nervous system disorders who have unmet medical needs. Headquartered in Switzerland and founded in 2015, NLS is led by an experienced management team with a track record of developing and commercializing product candidates. For more information, please visit . Safe Harbor Statement This press release contains expressed or implied forward-looking statements pursuant to U.S. federal securities laws. For example, NLS is using forward-looking statements when it discusses the potential benefits of Mazindol ER and the timing and expected format of the AMAZE Phase 3 clinical program. These forward-looking statements and their implications are based on the current expectations of the management of NLS only and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; NLS may encounter delays or obstacles in launching and/or successfully completing its clinical trials; NLS' products may not be approved by regulatory agencies, NLS' technology may not be validated as it progresses further and its methods may not be accepted by the scientific community; NLS may be unable to retain or attract key employees whose knowledge is essential to the development of its products; unforeseen scientific difficulties may develop with NLS' process; NLS' products may wind up being more expensive than it anticipates; results in the laboratory may not translate to equally good results in real clinical settings; results of preclinical studies may not correlate with the results of human clinical trials; NLS' patents may not be sufficient; NLS' products may harm recipients; changes in legislation may adversely impact NLS; inability to timely develop and introduce new technologies, products and applications; and loss of market share and pressure on pricing resulting from competition, which could cause the actual results or performance of NLS to differ materially from those contemplated in such forward-looking statements. Except as otherwise required by law, NLS undertakes no obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. More detailed information about the risks and uncertainties affecting NLS is contained under the heading "Risk Factors" in NLS' annual report on Form 20-F for the year ended December 31, 2022 filed with the Securities and Exchange Commission (SEC), which is available on the SEC's website, , and in subsequent filings made by NLS with the SEC. For additional information: Marianne Lambertson (investors & media) NLS Pharmaceutics Ltd. +1 239.682.8500 ml@nls-pharma.com SOURCE: NLS Pharmaceutics AG View source version on accesswire.com:

Whatever Roche has learned about Jnana Therapeutics’ drug discovery platform over the past two years, it’s intrigued enough to set up a second partnership. While the last deal had centered on solute carriers — or SLCs, the huge family of proteins that Jnana had built its name on — this time around, Roche wants to apply Jnana’s tech on a range of other hard-to-drug targets. The pharma giant will dish out $50 million upfront, plus “significant near-term milestone payments” and more than $2 billion in milestones. Alongside the deal, Jnana is also taking the wraps off a $107 million Series C that will fuel its internal efforts — particularly the lead program, an oral treatment for the rare metabolic disease phenylketonuria (PKU) currently in Phase I. Stuart Schreiber’s bid to tackle huge class of crucial proteins nabs another $50M The broadened scope of the new Roche deal parallels Jnana’s own move to go beyond SLCs and use its chemoproteomics platform, dubbed RAPID, to find molecules that can hit targets like transcription factors and signaling scaffold proteins, said Joel Barrish, president and CSO. Stuart Schreiber Barrish set out in 2017 with CEO Joanne Kotz and scientific co-founders Stuart Schreiber and Ramnik Xavier of the Broad to spotlight an unexplored protein territory by systematically studying over 400 SLC transporters. But since at least their last financing round in the summer of 2021, they’ve been hinting at how the platform has grown so powerful, it has the potential to drug virtually any protein. “SLCs are a really diverse class of proteins and all kinds of structures, all kinds of — different numbers of transmembrane domains, and different pharmacology,” he said. “And what we were finding as we were running through the RAPID platform with different SLCs is that it was just consistently being able to find modulators of SLCs that had, again, all different structures, and all different pharmacology. Some of them were just involved in protein-protein interaction; some of them were involved in transport of key metabolites. And because of that, we thought, you know, let’s look at other proteins and other protein classes.” Roche partners on a slate of Jnana's immunology, neurology targets, rewarding its faith in the SLC transporter class As in their last deal — which came with $40 million cash and $1 billion in milestones — Roche and Jnana will be looking at targets in neurology and immunology. But they’re also adding oncology to the menu. Once the drugs pass preclinical tests, Roche is responsible for development and commercialization. There’s still a number of SLC programs in the biotech’s internal pipeline as well, not least JNT-517, the PKU drug. Patients with PKU cannot break down phenylalanine, leading to dangerous buildup of the amino acid in blood and brain. The current standard of care, Barrish said, remains a strict low protein diet. JNT-517 is designed to block the SLC transporter SLC6A19, thereby inhibiting reabsorption of phenylalanine from the kidney back into the bloodstream. Compared to biologics such as enzyme replacement or gene therapies, Barrish said that JNT-517 represents an oral option that can be given to anyone with few limitations, regardless of their genetic background, including children — who make up a significant portion of the patient population. The drug has also been granted the rare pediatric disease designation by the FDA. Kotz added that the new round gives Jnana more than two years of runway, enough to bring the PKU program through Phase I clinical proof-of-concept and fund other drugs in immune-mediated diseases and cancer. Bain Capital Life Sciences led the round, and managing director Ron Renaud will be joining the board. Existing investors, including RA Capital Management, Polaris Partners, Versant Ventures, Avalon Ventures and Pfizer Ventures, also chipped in. Ultimately, Kotz and Barrish hope their biotech can contribute to what they see as a renaissance of small molecule drugs, with the advent of new modalities such as protein degraders and molecular glues. “As a small molecule chemist who has been involved in industry for about 40 years, it’s something I’ve always believed in,” Barrish said. “But, you know, there’s always waxing and waning of the strength of that belief, but I think that we’re back again. We’ve really shown how small molecules are just so, so important in terms of being able to go after targets that can be accessed by no biologics, cell therapy, and gene therapies, for example.”

Jnana Therapeutics is deepening its ties with Roche, revealing Tuesday its second deal with the Swiss pharmaceutical giant since 2020 alongside a fresh round of funding. In two separate announcements, Boston-based Jnana said it raised a $107 million Series C round and formed a new alliance with Roche to develop drugs aimed at targets in cancer, autoimmune and neurological diseases. The Roche deal brings an additional $50 million upfront into Jnanas coffers, with the potential of up to $2 billion more if certain milestones are met. All told, the company has now raised more than $200 million in private funding, and inked three partnerships, since its launch in 2017. The latest deals have extended its financial runway for an additional two years, according to Joanne Kotz, Jnanas co-founder and CEO. Jnana was formed based on the work of Broad Institute of MIT and Harvard researchers Stuart Schreiber and Ramnik Xavier. The biotech is one of several co-founded by Schreiber, who helped form Vertex Pharmaceuticals and Ariad Pharmaceuticals, among other companies. Its developing drugs that are meant to target solute carriers, or SLCs, a class of proteins that move molecules in and out of cells. Jnanas lead drug candidate, JNT-517, is in a Phase 1 trial for phenylketonuria, a rare genetic disease caused by an inability to metabolize the amino acid phenylalanine. JNT-517 is meant to work by blocking an SLC that causes the amino acid to build up in the bloodstream.Inhibiting that target, known as SLC6A19, should help decrease the levels of phenylalanine, said Joel Barrish, the companys co-founder and chief science officer. But that hasnt yet been proven.Frankly, [SLC6A19] has been previously a challenging drug target in that it's been known for a while, and no one's been able to identify a development candidate for [it], Barrish said.A readout is expected in the first half of 2023.Jnana is also working on four other drug candidates for undisclosed autoimmune disease and cancer targets in addition to the research its conducting with Roche.Roche initially gambled on Jnana in 2020, offering the startup $40 million in upfront payments to co-develop therapeutics for autoimmune and neurological conditions.The new deal expands those indications to include cancer, though neither company has announced specific disease targets.Jnana has a third partnership in place with Neurocrine Biosciences. The company hasnt ruled out future alliances with others, Kotz said.Theyve been wonderful partners, but we continue to think that theres partnership opportunities that we can take on in the future because of the breadth of the platform, Kotz said.Bain Capital Life Sciences led the Series C round, which also included investors such as RA Capital Management and the venture arms of AbbVie and Pfizer. '