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Item 1. Business

2023-03-24 compared with 2022-03-11 · 341 added, 406 removed, 603 unchanged (55% of the section changed)

Jaguar Health, Inc.

(“Jaguar” or the “Company”) is a commercial stage pharmaceuticals company focused on developing novel, plant-based, non-opioid, and sustainably derived prescription medicines for people and animals with GI distress, including chronic, debilitating diarrhea.

(“Jaguar” or the “Company”) is a commercial stage pharmaceutical company focused on developing novel, plant-based, sustainably derived prescription medicines for people and animals with gastrointestinal (“GI”) distress, including chronic, debilitating diarrhea.

Jaguar Health's wholly owned subsidiary, Napo Pharmaceuticals, Inc.

(“Napo”), focuses on developing and commercializing proprietary plant-based human pharmaceuticals from plants harvested responsibly from rainforest areas.

Our crofelemer drug product candidate is the subject of the OnTarget study, an ongoing pivotal Phase 3 clinical trial for prophylaxis of diarrhea in adult cancer patients receiving targeted therapy.

As announced, patient enrollment in OnTarget reached approximately 75% in February 2023, and target trial enrollment of 256 patients is expected to complete in the second quarter of 2023.

Jaguar is the majority shareholder of Napo Therapeutics S.p.A.

(“Napo Therapeutics”), an Italian corporation established by Jaguar in Milan, Italy in 2021 that focuses on expanding crofelemer access in Europe.

Napo Therapeutics’ core mission is to provide access to crofelemer in Europe to address significant rare/orphan disease

indications, including, initially, two key rare disease target indications:

Short bowel syndrome (“SBS”) with intestinal failure and congenital diarrheal disorders (“CDD”).

Jaguar Animal Health is a tradename of Jaguar Health.

Our wholly owned subsidiary, Napo Pharmaceuticals, Inc.

(“Napo”), focuses on developing and commercializing proprietary plant-based human pharmaceuticals for the global marketplace from plants or plant products used traditionally in rainforest areas.

Napo’s marketed drug Mytesi (crofelemer 125 mg delayed-release tablets) is a first-in-class oral botanical drug product approved by the U.S.

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To date, this is the only oral plant-based botanical prescription medicine approved under the FDA’s Botanical Guidance.

Jaguar Animal Health’s Canalevia-CA1 (crofelemer delayed-release tablets) drug is the first and only oral plant-based prescription product that is FDA conditionally approved to treat chemotherapy-induced diarrhea (“CID”) in dogs.

Canalevia-CA1

is a canine-specific formulation of crofelemer.

Napo Therapeutics S.p.A., Napo’s majority owned Italian subsidiary, focuses on expanding crofelemer access in Europe.

Jaguar, formerly known as Jaguar Animal Health, Inc., was founded in San Francisco, California as a Delaware corporation on June 6, 2013 (inception).

The Company was a majority-owned subsidiary of Napo until the close of the Company's initial public offering on May 18, 2015.

The Company was formed to develop and commercialize first-in-class prescription and non-prescription products for companion and production animals and horses.

The Company's first non-prescription commercial products, Neonorm Calf and Neonorm Foal, were launched in 2014 and 2016, respectively.

On July 31, 2017, Jaguar completed a merger with Napo pursuant to the Agreement and Plan of Merger dated March 31, 2017, by and among Jaguar, Napo, Napo Acquisition Corporation (“Merger Sub”), and Napo's representative (the “Merger Agreement”).

In accordance with the terms of the Merger Agreement, upon the completion of the merger, Merger Sub merged with and into Napo, with Napo surviving as the wholly-owned subsidiary (the “Merger” or “Napo Merger”).

Immediately following the Merger, Jaguar changed its name from “Jaguar Animal Health, Inc.” to “Jaguar Health, Inc.” Napo now operates as a wholly-owned subsidiary of Jaguar focused on human health including the ongoing development of crofelemer and commercialization of Mytesi.

On March 15, 2021, Jaguar established Napo EU S.p.A (which changed its name in January 2022 to Napo Therapeutics S.p.A.

“Napo Therapeutics”) based in Milan, Italy as a subsidiary of Napo.

Napo Therapeutics’ mission is to provide access to crofelemer in Europe to address significant rare/orphan disease indications, including, initially, two key orphan target indications:

Short bowel syndrome with intestinal failure (“SBS-IF”), and congenital diarrheal disorders (“CDD”).

On November 3, 2021, Napo Therapeutics merged with Dragon SPAC S.p.A.

(“Dragon SPAC”).

On December 13, 2021, the European Medicines Agency (“EMA”) granted orphan-drug designation (“ODD”) for crofelemer for short bowel syndrome (“SBS”) indication in the European Union following review of the ODD application Napo submitted to the EMA in September 2021.

Following this decision from the EMA, Napo Therapeutics is initiating efforts to commence clinical development of crofelemer in both adult and pediatric SBS patients in support of the company’s key focus on leveraging the EMA’s accelerated conditional marketing authorization pathway in Europe for these rare diseases.

Napo Therapeutics has also agreed to support an investigator-initiated trial (“IIT”) which will provide proof of concept (“POC”) support for potential expanded access programs for crofelemer for patients with CDD and/or SBS patients with intestinal failure (“IF”).

The expanded access program will be initiated following completion of this study and upon publication of POC results, potentially in 2023.

Crofelemer previously received ODD in the U.S.

from the FDA for SBS.

The Company’s Canalevia-CA1 (crofelemer delayed-release tablets) drug is the first and only oral plant-based prescription product that is FDA conditionally approved to treat chemotherapy-induced diarrhea (“CID”) in dogs.

Crofelemer was granted orphan drug designation (“ODD”) by the FDA in August 2017 and by the European Medicines Agency (“EMA”) in December 2021.

Crofelemer was granted ODD by the FDA in February 2023 for microvillus inclusion disease (“MVID”), a rare CDD condition, and granted ODD for MVID by the EMA in October 2022.

The Company is currently supporting investigator-initiated proof-of-concept (“POC”) studies of crofelemer in patients with SBS with intestinal failure or CDD, focused on obtaining POC of reduction of requirements of parenteral support including parenteral nutrition and/or intravenous fluids, throughout 2023.

In accordance with the guidelines of specific European Union countries, publications of POC data from these trials could support early patient access to crofelemer for SBS with intestinal failure or CDD through programs in Europe.

Early access programs are revenue generating, and reimbursable for participating patients.

Napo Therapeutics is initiating efforts to commence clinical development of crofelemer in SBS patients in support of the Company’s key focus on leveraging the EMA’s accelerated conditional marketing authorization pathway in Europe for these rare diseases.

SBS affects approximately 10,000 to 20,000 people in the U.S., according to the Crohn's & Colitis Foundation, and it is estimated that the population of SBS patients in Europe is approximately the same size.

Despite limited treatment options, the global SBS market exceeded $568 million in 2019 and is expected to reach $4.6 billion by 2027, according to a report by Vision Research Reports.

On December 21, 2021, we received conditional approval from the FDA to market Canalevia-CA1 (crofelemer delayed-release tablets), our oral plant-based prescription drug and the only drug for the treatment of CID in dogs.

We expect Canalevia-CA1 to be available to multiple leading veterinary distributors in the U.S.

in the second quarter of 2022 after we complete a post-approval update to the chemistry, manufacturing and controls (“CMC”) related to crofelemer.

This update will align with the CMC requirements related to crofelemer used as the active ingredient in Mytesi.

On January 4, 2022, we announced the launch of Canalevia-CA1 (crofelemer delayed-released tablets), which is being commercialized as a prescription drug product under the Company’s Jaguar Animal Health tradename.

CDD is considered an ultra-rare disease, with likely a couple of hundred patients diagnosed globally.

In February 2022, Napo announced the completion of an investigator-initiated preclinical enterocyte (intestinal cell) in vitro study to evaluate the effects of crofelemer on cells with certain genetic defects that result in specific forms of CDD.

The data from this study is expected to support the rare disease business model that Napo Therapeutics is pursuing in Europe under its exclusive license for crofelemer from Jaguar and Napo.

CDD patients have intestinal failure and morbidity resulting in a failure to thrive due to malabsorption of nutrients and need parenteral nutrition.

We believe the novel mechanism of action of crofelemer may have considerable potential to manage the severe secretory loss of electrolytes and fluid resulting in dehydration.

There are currently no therapies for CDD except parenteral nutrition.

Thus, crofelemer may reduce the associated morbidity and mortality of CDD and lessen the need for parenteral nutrition (“PN”).

Most of the activities of the Company are focused on the development and/or commercialization of Mytesi, including the ongoing clinical development of crofelemer for the prophylaxis of diarrhea in adult patients receiving targeted cancer therapy.

Napo’s pivotal OnTarget Phase 3 clinical trial of crofelemer for prophylaxis of cancer therapy-related diarrhea (“CTD”) was initiated in October 2020 and is expected to complete enrolment in 2 nd quarter of 2023.

We also support the prioritized clinical program at Napo Therapeutics centered around the POC investigator-initiated trials of Crofelemer for SBS and CDD.

In the field of animal health, we are continuing limited activities related to developing and commercializing first-in-class gastrointestinal products for dogs, dairy calves and foals.

Crofelemer is a novel, first-in-class anti-secretory antidiarrheal drug which has a normalizing effect on electrolyte and fluid balance in the gut, and this mechanism of action has the potential to benefit multiple disorders that cause gastrointestinal distress, including diarrhea and abdominal discomfort.

Mytesi is in development for multiple possible follow-on indications, including for the lead Phase 3 program in CTD, investigating prophylaxis of diarrhea related to targeted therapy with or without standard chemotherapy.

Crofelemer delayed-release tablets are also being evaluated in diarrhea-predominant irritable bowel syndrome (“IBS-D”) and idiopathic/functional diarrhea in investigator-initiated trials.

Crofelemer powder for oral solution is being developed to support orphan or rare disease indications for infants and/or children with SBS and/or CDD, such as MVID.

In addition, a second-generation proprietary anti-secretory antidiarrheal drug (“NP-300”) is in development for symptomatic relief and treatment of moderate-to-severe diarrhea, with or without concomitant antimicrobial therapy, from bacterial, viral and parasitic infections including Vibrio cholerae , the bacterium that causes cholera.

This program is being pursued with the targeted incentive from the FDA of tropical disease priority review voucher.

In January 2023, Jaguar and Filament Health (“Filament”), with Funding from One Small Planet, formed the U.S.-based joint venture Magdalena Biosciences, Inc.

(“Magdalena”).

Magdalena’s focus is on the development of novel, natural prescription medicines derived from plants for mental health indications including, initially, attention-deficit/hyperactivity disorder (“ADHD”) in adults.

The goal of the collaboration is to extend the botanical drug development capabilities of Jaguar and Filament in order to develop pharmaceutical-grade, standardized drug candidates for mental health disorders, and to partner with a potential future licensee to develop and commercialize these novel plant-based drugs.

This new venture aligns with Jaguar's mental health Entheogen Therapeutics Initiative (“ETI”) and Filament's corporate mission to develop novel, natural prescription medicines from plants.

Magdalena will leverage Jaguar's proprietary medicinal plant library and Filament's proprietary drug development technology.

Jaguar’s library of 2,300 highly characterized medicinal plants and 3,500 plant extracts, all from firsthand ethnobotanical investigation by Jaguar and members of the ETI Scientific Strategy Team, is a key asset we have generated over 30 years that bridges the knowledge of traditional healers and Western medicine.

Magdalena holds an exclusive license to plants and plant extracts in Jaguar's library, not including any sources of crofelemer or NP-300, for specific indications and is in the process of identifying plant candidates in the library that may prove beneficial for addressing indications such as ADHD.

In December 2021 we received conditional approval from the FDA to market Canalevia-CA1 (crofelemer delayed-release tablets), our oral plant-based prescription drug and the only available veterinary drug for the treatment of chemotherapy-induced diarrhea (“CID”) in dogs, and Canalevia-CA1 is now available to multiple leading veterinary distributors in the U.S.

Canalevia-CA1 is a tablet that is given orally and can be prescribed for home treatment of CID.

Canalevia-CA1 is a canine-specific formulation of crofelemer that is conditionally approved by the FDA under application number 141-552.

Conditional approval allows for commercialization of the product while Jaguar Animal Health continues to collect the substantial evidence of effectiveness required for a full approval.

Canalevia-CA1 is conditionally approved by the FDA under application number 141-552.

Conditional approval allows for commercialization of the product while Jaguar Animal Health continues to collect the substantial evidence of effectiveness required for full approval.

We have received Minor Use in a Major Species (“MUMS”) designation from the FDA for Canalevia-CA1 to treat CID in dogs.

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threshold for minor use in each of the seven major species covered by the MUMS act.

The small number threshold is currently 70,000 for dogs, representing the largest number of dogs that can be affected by a disease or

condition over the course of a year and still have the use qualify as a minor use.

We expect Canalevia-CA1 to be available to multiple leading veterinary distributors in the U.S.

in the second quarter of 2022 after we complete a post-conditional-approval update to the CMC related to crofelemer.

In the field of animal health, we are continuing limited activities related to developing and commercializing first in class gastrointestinal products for dogs, dairy calves, foals, and high value horses.

Most of the activities of the Company are focused on the commercialization of Mytesi and Canalevia-CA1 and the ongoing clinical development of crofelemer for the prophylaxis of diarrhea in adult patients receiving targeted cancer therapy.

In June 2021, Napo Pharmaceuticals recruited Dr.

Darlene Horton, as the Chief Medical Officer (“CMO”) of Napo Pharmaceuticals to support the ongoing clinical development activities for prescription products for human health.

Horton is a 25-year veteran of the biotech and pharmaceutical industry.

Prior to joining Napo, she led clinical development and regulatory strategy as CMO at Coherus Biosciences, Itero Biopharmaceuticals, and SMC Biotechnology.

As Head of Clinical and Medical Affairs at Scios, she led the clinical development program that led to the approval of Natrecor® and was on the senior executive team when Scios was acquired by JNJ for $2.4B.

At JNJ, she co-led (with strategic marketing) the cardiovascular therapeutic area when JNJ in-licensed and began developing the blockbuster drug Xarelto®.

She also served as CEO at Nile Therapeutics and TulangCo Inc.

Horton completed her Pediatric Cardiology fellowship and Pediatrics Residency at UCSF.

She holds M.D.

in Microbiology degrees from the University of Florida.

The small number threshold is currently 80,000 for dogs, representing the largest number of dogs that can be affected by a disease or condition over the course of a year and still have the use qualify as a minor use.

We believe Jaguar is poised to realize a number of synergistic, value adding benefits—an expanded pipeline of potential blockbuster human follow-on indications of crofelemer, and a second-generation anti-secretory agent—upon which to build global partnerships.

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Additionally, several of the drug product opportunities in Jaguar’s crofelemer pipeline are backed by Phase 2 and proof of concept evidence from human clinical trials.

Crofelemer is a novel, first in class anti secretory agent which has a normalizing effect on electrolyte and fluid balance while acting locally in the gut, and this mechanism of action has the potential to benefit multiple disorders that cause gastrointestinal distress, including diarrhea and abdominal discomfort.

Crofelemer is also in development for possible follow on indications, including prophylaxis for cancer therapy related diarrhea (“CTD”);

for rare disease indications for symptomatic treatment of infants and children with CDD and for adult and pediatric patients with SBS-IF.

As mentioned above, crofelemer has received ODD for SBS in the US and in the European Union (“EU”).

Furthermore, the drug is being evaluated for management of diarrhea and abdominal discomfort in inflammatory bowel disease (“IBD”);

diarrhea-predominant irritable bowel syndrome (“IBS-D”);

and for idiopathic/functional diarrhea.

A second generation proprietary anti secretory agent, NP-300 (lechlemer), is undergoing preclinical development for symptomatic relief and treatment of diarrhea in patients with acute infection from cholera.

Napo has a direct sales force of 8 sales representatives and a national sales director covering U.S.

geographies with the highest commercial potential.

In 2019, we hired Ian Wendt, an industry veteran with a broad range of experience that includes commercializing supportive care and HIV treatments, as Vice President of Commercial Strategy.

He was promoted to Chief Commercial Officer in 2020.

With support provided by concomitant marketing, promotional activities, patient education programs and peer education initiatives described below, we expect continued growth in the number of patients treated with Mytesi.

Wendt will lead disease state educational initiatives that will pave the way for crofelemer’s final development for the CTD market and our commercial role for this next important, potential indication for Mytesi.

Additionally, he is leading commercialization activities for Canalevia-CA1 in the U.S.

veterinary market.

A key component of our marketing strategies for Mytesi in 2021 was focused on the transition of Mytesi distribution to a closed network of specialty pharmacies rather than to wholesalers that resell the product to retail pharmacies.

A key component of our marketing strategies for Mytesi in 2022 was our focus on the transition of Mytesi distribution to a closed network of specialty pharmacies rather than to wholesalers that resell the product to retail pharmacies.

This transition was intended to help remove access barriers for patients receiving Mytesi and includes services such as a higher level of support for prior authorizations, appeals, adherence counseling, and home delivery options.

While patients often visit retail pharmacies for short-term or uncomplicated medical needs, specialty pharmacies focus on serving patients with complex and chronic medical conditions like HIV.

The transition to a closed network of specialty pharmacies is expected to result in a meaningful reduction in Mytesi distribution costs and

prepare our U.S.

commercial distribution network for future indication expansion of crofelemer to other populations of patients with complex medical needs.

However, when we made the full transition on September 3, 2021, to selling to specialty pharmacies, it resulted in an underrepresentation of actual Mytesi utilization, as wholesalers depleted their inventory during the transition process.

The goal of Napo’s sales team is to deliver a frequent and consistent selling message to targeted, high volume prescribers of HIV antiretroviral therapies (“ART”) and to gastroenterologists who see large numbers of HIV patients.

In 2017 we released the results of a survey of 350 people living with HIV and AIDS regarding the topic of “Talking to Your Doctor About Symptoms.” The survey results show that diarrhea remains prevalent in those living with HIV/AIDS, with 27% of respondents reporting that they currently have diarrhea, and 56% reporting that they have had diarrhea in the past.

Additionally, the results of a 2017 Napo sponsored survey of 271 U.S.

board certified gastroenterologists indicate that the number one GI complaint for people living with HIV/AIDS is diarrhea, and 93% of U.S.

gastroenterologists see patients with HIV/AIDS in their practice.

Key to the success of our sales representatives in growing Mytesi sales is segmenting and targeting the right health care providers—those HIV treaters who are high prescribers of ART and those gastrointestinal doctors who see large populations of people living with HIV/AIDS.

The target list of prescribers for our sales reps includes a pool of approximately 1,300 high volume ART prescribing HIV specialists, and gastroenterologists who see the largest number of people living with HIV/AIDs, and we’ve strategically focused our sales force in the US geographies with the highest potential, including San Francisco, Sacramento, Seattle, southern California, Arizona, Nevada, Florida, New York City/Long Island, Connecticut, New Jersey, Pennsylvania, Maryland, Kansas, Texas, Missouri, Chicago, Michigan, Atlanta, Louisiana, DC, Virginia, North Carolina, South Carolina, Indianapolis, and Ohio.

Medical education presentations led by health care providers (“HCPs”) participating in the Napo Speakers Bureau—a group that includes HIV/AIDS treaters, infectious disease specialists, gastroenterologists, colorectal surgeons, nurse practitioners, doctors of pharmacology, and physician assistants—focus on the prevalence and pathophysiology of gastrointestinal consequences of HIV infection and on the latest treatment options for HIV related diarrhea.

Presentations given by patient advocate members provide information to HIV/AIDS patients about the prevalence of diarrhea in people living with HIV/AIDS (“PLWHA”) and offer guidance about talking to HCPs regarding diarrhea related concerns.

The transition to a closed network of specialty pharmacies resulted in a meaningful reduction in Mytesi distribution costs and helps prepare our U.S.

commercial distribution network for future indication expansion of crofelemer to other populations of patients with complex medical needs, such as CTD.

With the introduction of newer antiretroviral (“ARV”) drug therapies, there has been a reduction in the severity of ARV induced diarrhea.

However, a significant portion of this patient population still suffers from diarrhea caused by HIV enteropathy, which is due to the direct and indirect effects of HIV on the intestinal mucosa.

Chronic diarrhea remains a significant complaint of PLWHA, particularly those who are older and have lived with the virus in their gut for 10+ years.

Chronic diarrhea remains a significant complaint of PLWHA, particularly those who are older and have lived with the virus in their gut for more than 10 years.

According to data from the U.S.

Centers for Disease Control and Prevention, currently more than 70% of people living with HIV are over age 50 and have lived with HIV for more than 10 years.

Napo is on many AIDS Drug Assistance Program (“ADAP”) formularies.

ADAPs provide lifesaving HIV treatments to low income, uninsured, and underinsured individuals living with HIV/AIDS in all 50 states and the territories.

The ADAP program provides Mytesi free of charge to patients who qualify and copay support for some patients who have insurance coverage.

Based on data from healthcare research firm Decision Resource Group, approximately 86% of ADAP eligible US lives now have access to Mytesi, which is now on the ADAP formularies for 30 states, including the four programs with the largest enrollment.

In May 2020, Napo launched a program to educate insurance companies about the benefits of Mytesi and negotiate better access to Mytesi for commercially insured patients.

We believed that our enhanced Mytesi market access strategy engaged select payors in contracting discussions with the objective of removing barriers for patients in order to allow them to more easily start on – and stay on – Mytesi.

This initiative represented a commercial opportunity to employ a strategic mechanism that was well-established in the U.S.

pharmaceutical industry to help patients access Mytesi.

Napo expanded the NapoCares Patient Support Program for Mytesi in April 2020 as part of the Company's enhanced market access strategy.

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The co-pay program and patient assistance program are components of a comprehensive suite of patient support services Napo rolled out in the second quarter of 2020 with the support of AssistRx, a specialty therapy initiation and patient support company.

On August 2021, Napo signed a license agreement with Napo EU S.p.A.

to study, develop, manufacture, and commercialize Napo’s plant-based crofelemer and lechlemer drug product candidates in the European Union (excluding Russia) and in specified non-EU countries in Europe for specific indications, which rights and obligations were assumed by the combined company formed by the merger of Napo Therapeutics with Dragon SPAC (the combined company uses the Napo Therapeutics name).

Per the terms of the license agreement, Napo will receive payment of up to $10 million as the initial license fee (to be paid in two installments, the first of which has already been received) as the initial license fee and is eligible to receive additional payments related to milestones, royalties, and product transfers.

In November 2021, Napo Therapeutics appointed Mr.

Massimo Mineo, a veteran of the European pharmaceutical industry for 20+ years, as general manager (the equivalent in Europe of chief executive).

He has significant experience in the field of orphan-drug development and commercialization activities and his leadership is expected to be instrumental in the ongoing development and commercialization activities for crofelemer for the planned SBS-IF indication in the EU.

Mineo is responsible for the strategy, planning, direction, and implementation of all Napo Therapeutics’ commercial, operational, and product development activities within Europe, with success defined by bringing crofelemer to market for key initial target indications, beginning with SBS-IF and CDD.

In November 2021, Napo Therapeutics announced the appointment of Annabella Amatulli as chief regulatory officer.

A recognized expert in global regulatory affairs, Ms.

Amatulli is responsible for both high-level strategic planning and hands-on support for Napo Therapeutics’ development programs and licensed products from a regulatory perspective and serves as the primary liaison between Napo Therapeutics and European health authorities.

In January 2022, Napo Therapeutics announced the appointment of Martire Particco, MD, a physician with 30+ years of experience in Europe’s pharmaceutical industry and in clinical practice, as its CMO for the EU-related development activities of Napo Therapeutics.

Particco possesses in-depth experience in the field of orphan and rare diseases, having been involved in the clinical development and launch of Pfizer’s pulmonary hypertension indication for sildenafil and the clinical development of Kerdion Biopharma’s ligneous conjunctivitis indication for plasminogen, with direct experience with patients and experts treating these rare pathologies.

In February 2022, Napo announced the completion of a third-party, investigator-initiated preclinical enterocyte (intestinal cell) in vitro study to evaluate the effects of crofelemer on cells with certain genetic defects that result in specific forms of CDD.

Jaguar believes that these study results will support certain requests received from the Office of Orphan Products Development at the U.S.

FDA in response to the ODD application Napo filed with the FDA for crofelemer for CDD in infants and children.

The data from this study will support the rare disease business model that Napo Therapeutics is pursuing in Europe under its exclusive license for crofelemer from Jaguar and Napo.

CDD patients have intestinal failure and morbidity resulting in a failure to thrive due to malabsorption of nutrients and need parenteral nutrition.

We believe the novel mechanism of action of crofelemer may have considerable potential to manage the severe secretory loss of electrolytes and fluid resulting in dehydration.

There are currently no therapies for CDD except parenteral nutrition.

Thus, crofelemer may reduce the associated morbidity and mortality of CDD and lessen the need for total parenteral nutrition (“TPN”).

Napo has actively ensured that its intellectual property (“IP”) filings in support of the development of crofelemer for various proposed indications are protected appropriately.

The IP portfolio for crofelemer includes the relief and treatment of HIV-associated diarrhea and chemotherapy-induced diarrhea as well as planned indications for inflammatory diarrhea, IBS-D, CID and SBS, with all indications, Napo prioritizes IP protection.

The IP portfolio for crofelemer includes the relief and treatment of HIV-associated diarrhea and CID as well as planned indications for inflammatory diarrhea, IBS-D, CDD and SBS, with all indications, Napo prioritizes IP protection.

Napo currently holds approximately 145 patents, the majority of which do not expire until 2027-2031, and approximately 53 patents pending.

In October 2020, Napo initiated its pivotal Phase 3 clinical trial of crofelemer (Mytesi) for prophylaxis of diarrhea in adult cancer patients receiving targeted therapy (OnTarget study).

The Phase 3 OnTarget clinical trial is a 24-week (two 12-week stages), randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of crofelemer in the prophylaxis of diarrhea in adult cancer patients with solid tumors receiving targeted cancer therapy-containing treatment regimens.

Patients will be randomized to receive either crofelemer or matching placebo treatment that will start concurrently with the initiation of targeted cancer therapy regimen.

In October 2020, Napo initiated its pivotal OnTarget Phase 3 clinical trial of crofelemer for prophylaxis of diarrhea in adult cancer patients receiving targeted therapy with or without chemotherapy.

As announced, patient enrollment in OnTarget reached approximately 75% in February 2023, and target trial enrollment of 256 patients is expected to complete in the second quarter of 2023.

The Company’s efforts over the past year were focused on expanding the trial to new U.S.

and international sites – with trial sites now active in Georgia, the Republic of Serbia, Argentina, and Taiwan—which has significantly accelerated enrollment.

The OnTarget trial is evaluating crofelemer's effectiveness in prophylaxis of diarrhea in adult solid tumor patients that receive targeted therapies with or without standard chemotherapy.

Such prophylaxis would potentially impact the patient's ability to remain on their cancer therapy regimens at approved doses for better cancer treatment outcomes, with less required medical intervention and cost.

The OnTarget clinical trial is a 24-week (two 12-week stages), randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of crofelemer in the prophylaxis of diarrhea in adult cancer patients with solid tumors receiving targeted cancer therapy-containing treatment regimens.

Patients are randomized to receive either crofelemer or matching placebo treatment that starts concurrently with the initiation of targeted cancer therapy regimen.

The primary endpoint will be assessed at the end of the initial (Stage I) 12-week double-blind placebo-controlled primary treatment phase after the last patient has completed 12 weeks of treatment.

After completing the Stage I treatment phase, the subjects will have the option to remain on their assigned treatment arm and reconsent to enter into the Stage II 12-week extension phase.

The safety and efficacy of orally administered crofelemer will be evaluated for the prophylaxis of diarrhea in adult cancer patients receiving targeted cancer therapies with or without standard chemotherapy regimens.

The assessment of the frequency of diarrhea will be measured by the average number of weekly loose and/or watery stools for the active (crofelemer) or placebo arms over 12-week Stage I treatment period.

A significant proportion of patients undergoing cancer therapy experience diarrhea.

Novel “targeted cancer therapy” agents, such as epidermal growth factor receptor (“EGFR”) antibodies and tyrosine kinase inhibitors (“TKIs”), with or without cycle chemotherapy agents, may activate intestinal chloride ion channel-mediated secretory pathways leading to increased electrolyte and fluid content in the gut lumen, which results in passage of loose/watery stools, i.e., secretory diarrhea.

With increased approval of several novel targeted therapies, it is estimated that 13.6% of cancer patients in 2020 were eligible for targeted therapies with or without standard chemotherapy regimens, according to a paper published in April 2021 in the journal Annals of Oncology 1 .

After completing the Stage I treatment phase, the subjects will have the option to remain on their assigned blinded treatment arm and reconsent to enter into the Stage II 12-week extension phase.

The assessment of prophylactic effects on diarrhea will be measured by the average number of weekly loose and/or watery stools for the active (crofelemer) or placebo arms over 12-week Stage I treatment period.

A significant proportion of patients undergoing cancer therapy experience diarrhea, which has the potential to cause dehydration, potential hospitalization, and non-adherence to treatment in this population.

Novel "targeted cancer therapy"

agents, such as epidermal growth factor receptor (EGFR) antibodies and tyrosine kinase inhibitors (TKIs), with or without cycle chemotherapy agents, may cause increased electrolyte and fluid content in the gut lumen, which results in passage of loose/watery stools (i.e., diarrhea).

Diarrhea has been reported as one of the most common side effects of TKIs and may result in cancer therapy drug holidays or reductions from therapeutic dose, potentially impacting patient outcomes.

Diarrhea is also a common side effect of some approved CDK 4/6 inhibitors.

published in April 2021 in the journal Annals of Oncology 1 .

According to the National Cancer Institute, in 2020, 1,806,590 new cases of cancer were diagnosed and nearly 250,000 of these newly diagnosed patients could be eligible for available targeted therapies.

Due to the chronic dosing and toxicity associated with targeted therapies, many cancer patients on targeted therapy require drug holidays or dose reductions in their therapy, including those due to diarrhea.

By improving stool consistency and reducing the frequency of watery stools, crofelemer is expected to provide improved adherence to the therapeutic dosing of any targeted therapies, potentially leading to better clinical outcomes.

We have learned from business development discussions with cancer drug manufacturers that the adoption and continued use of targeted cancer therapies is directly related to the ability of patients to tolerate these therapies—highlighting the importance of supportive care drugs like crofelemer to help manage cancer treatment-related diarrhea in this patient population.

As previously announced, an abstract regarding patient outcomes associated with cancer-related diarrhea (“CRD”) by Napo and Napo's collaborators was accepted for poster presentation at the American Society of Clinical Oncology (ASCO®) Annual Meeting, which was held virtually from June 4-8, 2021.

This study found that patients with CRD were 40% more likely to discontinue the chemotherapy or targeted therapy than patients without CRD.

By improving stool consistency and reducing the frequency of loose/watery stools, crofelemer is expected to provide improved adherence to the therapeutic dosing of any targeted therapies, potentially leading to better clinical outcomes.

We have learned from discussions with cancer drug manufacturers that the adoption and continued use of targeted cancer therapies is directly related to the ability of patients to tolerate these therapies—highlighting the importance of supportive care drugs like crofelemer to help manage cancer treatment-related diarrhea in this patient population.

As previously announced, it has been reported that patients with cancer related diarrhea (CRD) were 40% more likely to discontinue the chemotherapy or targeted therapy than patients without CRD.

The persistence of index cancer therapy and time to switch were also lower for patients with CRD.

Strategies to control CRD and continue cancer therapy are urgently needed 2 .

In addition, two CRD-related abstracts from Napo and its collaborators were accepted for online publication at ASCO.

One of these studies found that patients with CRD used significantly more resources, including outpatient services, ED visits, and hospitalizations.

Effective prevention of CRD remains an unmet strategy to reduce the overall

Furthermore, it has been reported that patients with CRD used significantly more resources, including outpatient services, emergency room visits, and hospitalizations.

Effective prevention of CRD provides an untapped market opportunity to reduce the overall cost of cancer care 3 .

Findings from studies have indicated that patients with CRD had nearly 2.9 times higher all-cause total cost of care than patients without CRD after adjusting for covariates.

Thus, prophylaxis of CRD is expected to result in a significant reduction in cancer-treatment cost 4 .

As previously announced results from a dog study of crofelemer and an irreversible pan-HER2+ tyrosine kinase inhibitor (TKI), neratinib, provide further scientific support for the evaluation of crofelemer in providing symptomatic relief of watery diarrhea in patients receiving a targeted cancer therapy drug like neratinib with or without cycle chemotherapy, without the use of loperamide, an antimotility drug.

The dog study was conducted without the prophylaxis or concomitant use of loperamide and demonstrated that crofelemer caused an approximate 30% reduction in the incidence and severity of diarrhea associated with daily oral administration of neratinib, within the 28-day treatment period.

Crofelemer also demonstrated significant improvement in the proportion of “responder” dogs, and there was a trend for fewer neratinib dose reductions in crofelemer treatment groups when compared to the control group.

Crofelemer was evaluated in a Phase 2 clinical study (called HALT-D), for the effectiveness of crofelemer for reduction of diarrhea in HER2 positive breast cancer patients receiving trastuzumab, pertuzumab, and chemotherapy agents such as docetaxel or pacilitaxel with or without carboplatin.

These therapies cause CID in up to 80% of breast cancer patients, reaching grade 3, which often requires hospitalization, in 8-12% of patients.

No antidiarrheal medications are currently approved that specifically target the underlying mechanism of CID associated with pertuzumab-containing regimens.

The results of the study were published in October 2022 and showed that prophylaxis with crofelemer resulted in substantial reduction of higher grade diarrhea compared to the standard-of-care control group patients.

Recent studies have shown that EGFR inhibitors cause increased chloride secretion into the lumen of the gut and that crofelemer, through its unique and novel mechanism of normalizing the chloride-secretory actions of the cystic fibrosis transmembrane conductance regulator (“CFTR”) and calcium-activated chloride channels (CaCC), is

Prasad, Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020

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Real world evidence

cost of cancer care 3 .

Findings from the other study indicated that patients with CRD had nearly 2.9 times higher all-cause total cost than patients without CRD after adjusting for covariates.

Prevention of CRD may result in a significant reduction in cancer-treatment cost 4 .

As previously announced in June 2020, the effects of crofelemer (Mytesi) were evaluated in reducing diarrhea associated with the irreversible pan-HER TKI neratinib in female dogs.

The data were presented at the American Association for Cancer Research (“AACR”) Annual Meeting II in 2020.

The results from the dog study provide further scientific support for the evaluation of crofelemer in providing symptomatic relief of watery diarrhea in patients receiving a targeted cancer therapy drug like neratinib with or without cycle chemotherapy, without the use of antimotility drugs like loperamide, in future clinical studies.

Crofelemer also demonstrated significant improvement in the proportion of responder dogs, and there was a trend for fewer neratinib dose reductions in both crofelemer treatment groups when compared to the control group.

The results and finding from a clinical, third-party investigator-initiated Phase 2 study (called HALT-D) evaluated the effectiveness of crofelemer for reduction of diarrhea in HER2 positive breast cancer patients receiving trastuzumab, pertuzumab, and chemotherapy agents such as docetaxel or pacilitaxel with or without carboplatin.

The investigators of the HALT-D study, sponsored by Georgetown University and funded by Genentech, a member of the Roche Group, were presented at the San Antonio Breast Cancer Symposium on December 10, 2021.

It has been reported that these pertuzumab-containing regimens cause diarrhea in up to 80% of breast cancer patients and approximately 8 to 12% of patients reach grade 3, which often requires hospitalization.

No antidiarrheal medications are currently approved that specifically target the underlying mechanism of CID associated with pertuzumab-containing regimens.

Recent studies have shown that EGFR inhibitors cause increased chloride secretion into the lumen of the gut and Crofelemer through its unique and novel mechanism of reducing the chloride-secretory actions of the cystic fibrosis transmembrane conductance regulator (“CFTR”) and calcium-activated chloride channels (CaCC), was considered to be mechanistically- and physiologically-appropriate for reducing the loss of electrolyte and fluid in breast cancer patients receiving this regimen.

The Principal Investigator (“PI”), Paula Pohlmann, MD, PhD, Associated Professor at the University of Texas MD Anderson Cancer Center and formerly from Georgetown University, reported the results of the HALT-D study.

This clinical study evaluated 51 breast cancer patients that were eligible to receive at least three cycles of pertuzumab-containing regimen with chemotherapy that were randomly assigned to either crofelemer in cycles 1 and 2 or the control group, in which patients received standard of care.

Breakthrough anti-diarrheal medicines (“BAM”) were permitted but not given prophylactically.

Findings showed that the primary endpoint, the incidence of diarrhea for at least two consecutive days, was not statistically different for the two groups.

However, crofelemer patients demonstrated significantly better outcomes compared to control group patients across a number of key secondary endpoints including reductions in the incidence and severity of diarrhea in cycle 2 based on Investigator and Patient Reported Outcomes (“PRO”) (see Jaguar Health's November 19, 2021 press release).

In the presentation, additional findings were reported that showed that CID occurred significantly lesser (by 23%) in the crofelemer group during cycle 1 and crofelemer patients were 1.8 times more likely than control patients to have their diarrhea resolved.

These data provide concordance to the planned primary endpoint in Napo’s ongoing phase 3 OnTarget study.

Pohlmann commented that the HALT-D study showed benefits of crofelemer across a range of important diarrhea-related measures, including its incidence, severity and probability of resolving and that the lack of difference in the primary endpoint was because about 70% of the patients in both groups would have at least two consecutive days of diarrhea regardless of cycle or CID treatment group.

The incidence of two consecutive days of diarrhea is

3 Lee Schwartzberg, M.D., FACP, Eric Roeland, M.D., FAAHPM, Pablo C.

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Okhuysen, M.D., Lee Schwartzberg, M.D., FACP, Healthcare utilization and costs associated with cancer-related diarrhea

typical in cancer patient experiences from receiving chemotherapy regimens and is thus not clinically relevant as it does not differentiate the severity nor duration of CID among treatment groups.

Pohlmann also commented that the secondary endpoints provided a more relevant assessment of CID, which may guide future studies that address this significant comorbidity in cancer patients receiving such regimens.

Napo is also continuing to conduct preclinical and formulation activities to support the evaluation of its second generation, plant-based oral prescription drug product, NP-300 (lechlemer), for its planned evaluation in the symptomatic treatment of diarrhea associated with acute infections including that from Vibrio cholerae.

considered to be mechanistically- and physiologically-appropriate for reducing the loss of electrolyte and fluid in breast cancer patients receiving this regimen.

As announced October 26, 2022, the results of the HALT-D trial were published in the peer reviewed journal Breast Cancer Research and Treatment.

This HALT-D study evaluated 51 breast cancer patients who were eligible to receive at least three cycles of pertuzumab-containing regimen with chemotherapy that were randomly assigned to either crofelemer in cycles 1 and 2 or the control group, in which patients received standard of care.

Breakthrough anti-diarrheal medicines (“BAM”) were permitted but not given prophylactically.

Findings showed that the primary endpoint, the incidence of diarrhea for at least two consecutive days, was not statistically different for the two groups.

However, crofelemer patients demonstrated significantly better outcomes compared to control group patients across a number of key secondary endpoints including reductions in the incidence and severity of diarrhea in cycle 2 based on Investigator and Patient Reported Outcomes (see Jaguar Health's November 19, 2021 press release).

The study also showed that CID occurred significantly lesser (by 23%) in the crofelemer group during cycle 1 and crofelemer patients were 1.8 times more likely than control patients to have their diarrhea resolved.

These data provide POC support to the primary endpoint in Napo’s ongoing phase 3 OnTarget clinical study.

Napo completed its requisite preclinical and formulation activities to support the Investigational New Drug (IND) application for its second-generation, plant-based oral prescription drug product, NP-300, for its clinical development for the symptomatic relief and treatment of moderate-to-severe diarrhea, with or without concomitant antimicrobial therapy, from bacterial, viral and parasitic infections including Vibrio cholerae , the bacterium that causes cholera.

As announced in September 2022, the FDA has activated the Company’s Investigational New Drug (IND) application for NP-300and the FDA concluded that Napo may proceed with its proposed phase 1 clinical trial for NP-300.

Following the completion of the phase 1 trial, the Company will be positioned to initiate the next stage of our clinical development program for cholera-related diarrhea when our development team has the requisite resources and bandwidth to initiate the additional required trials.

Cholera produces a devastating loss of electrolytes and fluid in patients and without appropriate reduction in loss of fluid and electrolytes, patients experience significant hospitalization and mortality.

Lechlemer provides the opportunity to treat cholera patients in combination with oral rehydration salts (“ORS”) and the recommended guidelines from the World Health Organization (“WHO”) for the use of appropriate antibiotics to reduce the burden of the pathogen.

Appropriate preclinical toxicity studies and formulation development activities are ongoing to support the conduct of clinical studies with lechlemer.

As previously mentioned, Napo completed 7-day and 28-day preclinical toxicology and safety studies in rats and dogs with lechlemer (NP-300) following repeated daily oral dosing.

Napo received partial support for preclinical services from the National Institute of Allergy and Infectious Diseases (“NIAID”) of the National Institutes of Health, and Napo is grateful for their partial support of lechlemer’s development.

Napo is currently conducting additional, prerequisite IND-enabling toxicity studies and also developing appropriate oral solid dosage forms to allow the clinical evaluation of lechlemer.

The Company plans to provide appropriate regulatory documents by end of the second quarter of 2022 to support the initiation of first-in-human (“FIH”) evaluation in the third quarter of 2022.

NP-300 provides the opportunity to treat cholera patients in combination with oral rehydration salts (“ORS”) and the recommended guidelines from the World Health Organization (“WHO”) for the use of appropriate antibiotics to reduce the burden of the pathogen.

Appropriate preclinical toxicity studies and formulation development activities are ongoing to support the conduct of clinical studies with NP-300.

Napo received partial financial support for preclinical services from the National Institute of Allergy and Infectious Diseases (“NIAID”) of the National Institutes of Health, and Napo is grateful for their support of NP-300’s development.

Cholera is an acute diarrheal illness caused by infection of the intestine with the bacterium Vibrio cholerae .

According to the Centers for Disease Control and Prevention of the U.S.

Department of Health & Human Services, an estimated 3 5 million cholera cases and more than 100,000 cholera-related deaths occur each year around the world.

Department of Health & Human Services, an estimated 1.3 to 4 million people around the world get cholera each year and 21,000 to 143,000 people die from it.

The infection is often mild or without symptoms but can sometimes be severe.

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According to the Brookings Institution, cholera continues to spread in Yemen, with 180,000 new cases reported in the first eight months of 2020.

We expect that lechlemer will be significantly less expensive and would support development efforts to receive a tropical disease priority review voucher from the FDA for an indication for the symptomatic treatment of diarrhea from acute infections such as cholera.

We expect that NP-300 will be significantly less expensive and would support development efforts to receive a tropical disease priority review voucher from the FDA for an indication for the symptomatic treatment of diarrhea from acute infections such as cholera.

Priority review vouchers are granted by the FDA as an incentive to develop treatments for neglected diseases and rare pediatric diseases.

Priority review vouchers are transferable and, in past transactions by other companies, have sold for prices ranging from $60 million to $350 million.

Additionally, we believe lechlemer may provide a long-term pipeline opportunity as a second-generation anti-secretory agent for multiple gastrointestinal diseases—especially in resource-constrained countries.

Napo received advice from the Division of Anti-Infectives at the U.S.

FDA in September 2021 as part of the pre-investigational New Drug Application (“Pre-IND”) discussion.

Napo plans to include the advice in its plans for the Phase 1 clinical trial in healthy volunteers, currently planned the second half of 2022.

The NP-300 (lechlemer) program is paired with funding from a promissory note related to the potential future sale of a possible TDPRV.

Priority review vouchers are transferable and, in past

transactions by other companies, have sold for prices ranging from $60 million to $350 million.

Additionally, we believe NP-300 may provide a long-term pipeline opportunity as a second-generation anti-secretory agent for multiple gastrointestinal diseases—especially in resource-constrained countries.

The NP-300 program is paired with funding from a promissory note related to the potential future sale of a possible TDPRV.

As previously announced, the Company also launched the Entheogen Therapeutics (“ETI”) initiative to support the discovery and development of novel, natural medicines derived from psychoactive and psychedelic plant compounds for treatment of mood disorders, neuro-degenerative diseases, addiction, and other mental health disorders.

The initiative is initially focused on plants with the potential to treat depression and leverages Napo’s proprietary library of approximately 2,300 plants with medicinal properties.

According to statistics available from the

National Institute of Mental Health Disorders, part of the National Institutes of Health, approximately 9.5% of American adults ages 18 and over will suffer from a depressive illness (major depression, bipolar disorder, or dysthymia) each year.

According to statistics available from the National Institute of Mental Health Disorders, part of the National Institutes of Health, approximately 9.5% of American adults ages 18 and over will suffer from a depressive illness (major depression, bipolar disorder, or dysthymia) each year.

Field research collaborations have been conducted in the past by members of the scientific strategy team (“SST”) of Jaguar’s predecessor company Shaman Pharmaceuticals, who are also members of the ETI SST, yielded possible applications for a compound called alstonine.

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The ETI SST consists of leading and globally renowned ethnobotanists, physicians, and pharmacologists as well as experts in the fields of natural product chemistry and neuropharmacology.

We believe the wealth of expertise, experience, and commitment of the ETI SST—comprised of multiple members of the original SST that contributed to development of Jaguar's proprietary library of approximately 2,300 plants—will play an instrumental role in advancing our shared initial goal of identifying plants in our library that may have the potential to treat mood disorders and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic sclerosis.

We believe the wealth of expertise, experience, and commitment of the ETI SST—comprised of multiple members of the original SST that contributed to development of Jaguar's proprietary library of plants—will play an instrumental role in advancing our shared initial goal of identifying plants in our library that may have the potential to treat mood disorders and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic sclerosis.

Mood disorders and neurodegenerative diseases affect hundreds of millions of people around the globe and represent classic unmet medical needs.

While Napo and Jaguar remain steadfastly focused on the commercial success of Mytesi and Canalevia-CA1, respectively, and on the development of potential crofelemer follow-on indications in the area of gastrointestinal treatments, the Company believes the same competencies and multi-disciplinary scientific strategy that led to the development of crofelemer will support collaborative efforts with potential partners to develop novel first-in-class prescription medicines derived from psychoactive plants.

While Napo and Jaguar remain steadfastly focused on the commercial success of Mytesi and on the potential development of crofelemer for CTD and the rare disease indications of SBS with intestinal failure and CDD, the Company believes the same competencies and multi-disciplinary scientific strategy that led to the successful development of Mytesi will support collaborative efforts with potential partners—such as the recently formed joint venture Magdalena Biosciences—to develop novel first-in-class prescription medicines derived from plants.

Our management team has significant experience in gastrointestinal product development for both humans and animals.

Napo was founded 32 years ago to perform drug discovery and development by leveraging the knowledge of traditional healers working in rainforest areas.

Napo was founded more than 30 years ago to perform drug discovery and development by leveraging the knowledge of traditional healers working in rainforest areas.

Ten members of the Jaguar and Napo team have been together for more than 15 years.

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Tyler Commercial Investment in Phytomedicinal Research Award in recognition of Napo’s ongoing commitment to the sustainable development and production of natural therapeutic preparations.

Specifically, this award acknowledges the successful development and approval of crofelemer, which is derived from the medicinal Croton lechleri tree in the Amazon rainforest.

Specifically, this award acknowledges the successful development and approval of crofelemer, which is derived from the Croton

lechleri tree in the Amazon rainforest.

Previous recipients of this award include Jaguar’s partner, Italy based Indena S.p.A., one of the world’s largest producers of clinically-tested botanical extracts for the food, dietary supplement, cosmetic, and pharmaceutical markets.

Pipeline within a product—crofelemer

Crofelemer is currently being evaluated for the prophylaxis of CTD in adult patients receiving targeted therapy.

As announced in October 2020, Napo has initiated its pivotal Phase 3 clinical trial of crofelemer (Mytesi) for prophylaxis of diarrhea in adult cancer patients receiving targeted therapy (OnTarget study).

Pipeline development opportunities for crofelemer

Crofelemer is currently being evaluated for the prophylaxis of CTD in adult solid tumor patients receiving targeted therapy with or without standard chemotherapy.

A significant proportion of patients undergoing cancer therapy experience diarrhea.

Novel targeted cancer therapy agents, such as epidermal growth factor receptor antibodies and tyrosine kinase inhibitors, with or without cycle chemotherapy agents, may

activate intestinal chloride secretory pathways leading to increased chloride secretion into the gut lumen, coupled with significant loss of water that would result in secretory diarrhea.

Novel targeted cancer therapy agents, such as epidermal growth factor receptor and tyrosine kinase inhibitors, may activate intestinal chloride secretory pathways leading to increased chloride secretion into the gut lumen, coupled with significant loss of water that would result in secretory diarrhea.

According to data appearing in “Treatment Guidelines for CID” (chemotherapy-induced diarrhea) in the April 2004 issue of Gastroenterology and Endoscopy News, diarrhea is the most common adverse event reported in chemotherapy patients.

Approved third-party supportive care products for chemotherapy-induced nausea and vomiting (“CINV”) include Sustol, Aloxi, Akynzeo and Sancuso.

According to a report published by Allied Market Research, the global CINV market was valued at $1.66 billion in 2015 and is estimated to reach $2.66 billion by 2022.

According to a market research report by iHealthcareAnalyst, Inc., the global market for CINV drugs is estimated to reach a value of $3.9 billion by 2029.

Diarrhea has been reported as the most common side effect of the recently approved CDK 4/6 inhibitor abemaciclib and the pan HER TKI neratinib, with occurrence ranging from 86% to >95% and grade 3 over 40%, in published studies.

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A novel antidiarrheal like crofelemer may hold promise for treating secretory diarrhea—and therefore also support long term cancer treatment adherence—in this population.

Napo has previously received orphan drug designation from the FDA for adult and/or pediatric SBS.

The Orphan Drug Act provides for granting special status to a drug or biological product to treat a rare disease or condition upon request of a sponsor.

Orphan drug designation qualifies the sponsor of the drug for various development incentives, including extended exclusivity, tax credits for qualified clinical testing, and relief of filing fees.

As mentioned above, Napo Therapeutics has licensed the rights for the orphan and rare diseases associated with SBS and CDD with IF.

Napo Therapeutics expects that an IIT in pediatric patients with CDD will study crofelemer in the second half of 2022.

This study will be initiated in the Middle East/North Africa (“MENA”) region with sites that treat infants and children with CDD and SBS with IF.

Crofelemer was granted ODD for SBS by the FDA in August 2017 and by the EMA in December 2021.

Crofelemer was granted ODD by the U.S.

FDA in February 2023 for MVID, a rare CDD condition, and crofelemer received ODD for MVID from the EMA in October 2022.

The Company is currently supporting investigator-initiated POC studies of crofelemer in patients with SBS with intestinal failure or CDD, focused on obtaining POC of reduction of requirements of parenteral support including parenteral nutrition and/or intravenous fluids, throughout 2023.

Early access programs are revenue generating, and reimbursable for participating patients.

The Orphan Drug Act (“ODA”) in the US provides for granting special status to a small molecule drug or biological product to treat a rare disease or condition upon request of a sponsor.

This status is referred to as ODD (or sometimes "orphan status").

ODD qualifies the sponsor of the drug for various development incentives, including tax credits for qualified clinical testing and relief of filing fees.

Additionally, the ODA provides a seven-year period of marketing exclusivity to the first sponsor who obtains marketing approval for a designated orphan drug.

In the EU, receipt of ODD supports some specific regulatory pathways, and sponsors who obtain ODD for their drug can benefit from Scientific Advice from the EMA for clinical trials for the orphan indication and receive market exclusivity for a period of ten years once the medicine is approved for commercialization.

CDD is a group of rare, chronic intestinal channel diseases, with onset in early infancy, that are characterized by severe, lifelong diarrhea and a lifelong need for nutritional intake either parenterally or with a feeding tube.

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As previously announced (in 2019), a clinical research study sponsored by The University of Texas Health Science Center at Houston (“UTHealth”) is being supported by Napo.

This study evaluates the safety and effectiveness of crofelemer for treatment of chronic idiopathic diarrhea in patients.

This study evaluates the safety and

effectiveness of crofelemer for treatment of chronic idiopathic diarrhea in patients.

Chronic idiopathic diarrhea is a common complaint of patients presenting to family practitioners and internists and is one of the most common reasons for referral to gastroenterologists.

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Crofelemer is also being evaluated in another investigator-initiated trial for the management of functional diarrhea in non-HIV patients.

The principal investigator for this clinical study is Dr.

Anthony Lembo, Professor, Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

This study is being conducted at the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

This clinical study is a randomized double-blind, placebo-controlled study in adult subjects with functional diarrhea.

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This approval was on the basis of the drug’s safety and efficacy in reducing the number of weekly and daily watery stools in patients and improvement of stool consistency, from unformed to formed stools, over a 24-week treatment period.

Unlike other available diarrhea treatments, crofelemer does not act by inhibiting intestinal motility.

Unlike other available diarrhea remedies, crofelemer does not act by inhibiting intestinal motility.

It has minimal oral absorption and does not have any clinically significant food or drug interactions, thereby allowing patients to maintain their appropriate dosing of treatment to suppress their viral load and maintain adequate CD4 levels in PLWHA.

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Moreover, it is not an opioid, like other traditionally used treatments, thus avoiding both the acute side effect of constipation and the potential for abuse.

Napo’s Scientific Advisory Board has focused primarily on physician education, and community and global awareness regarding the importance and availability of solutions for neglected comorbidities, such as the first in class anti secretory mechanism of action of Mytesi for its currently approved indication.

There are significant barriers to entry for Mytesi (crofelemer).

Through Napo, we hold an extensive global patent portfolio.

There are significant barriers to entry for generic competition for Mytesi (crofelemer).

Napo holds an extensive global patent portfolio.

At the present time, we hold approximately 145 issued worldwide patents, with coverage in many cases that extends until 2031.

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The FDA requires that the manufacturer of crofelemer use a validated proprietary bioassay to release the drug substance and drug product of Mytesi.

While most generic products are fashioned to meet chemical release specifications that are in the public domain, the specifics of this assay are not publicly available.

While most generic products are fashioned to meet chemical release specifications that are in the public domain, the specifics of this assay are not

publicly available.

There is no pathway by which a generic product can be developed for a drug approved under botanical guidance.

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A generic player would have to conduct costly and risky clinical trials.

While Jaguar’s commercial and development efforts have evolved to focus primarily on Mytesi and human pipeline indications since its merger with Napo, the Company has commenced launch initiatives related to Canalevia-CA1, our drug product which received conditional approval in December 2021 for treatment of CID in dogs.

CID in dogs is typically caused by the same mechanism of action as in humans, and hence the work in dogs serves as a

preclinical proof of concept for the diarrhea in humans that is related to targeted cancer therapy.

While Jaguar’s commercial and development efforts have evolved to focus primarily on Mytesi and human pipeline indications since its merger with Napo, the Company commenced launch initiatives related to Canalevia-CA1, our drug product which received conditional approval in December 2021 for treatment of CID in dogs.

CID in dogs is typically caused by the same mechanism of action as in humans, and hence the work in dogs serves as a preclinical proof of concept for the diarrhea in humans that is related to targeted cancer therapy.

CID is an interesting model for human medical need and is being pursued as a prescription indication for animal health.

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As previously announced, Jaguar has received MUMS designation status from the FDA for Canalevia-CA1 for the indication of CID in dogs.

MUMS designation is modeled on the orphan drug designation for human drug development and offers possible financial incentives to encourage MUMS drug development, such as the availability of grants to help with the cost of developing the MUMS drug.

For Jaguar Animal Health’s second proposed indication for Canalevia, exercise induced diarrhea (“EID”) in dogs, the Company is leveraging the use of many of the same major technical sections that have been submitted in support of the Company's application for Canalevia-CA1 for the indication of CID in dogs.

Conditional approval of Canalevia for EID, under the name Canalevia-CA2, is expected in the fourth quarter of 2022.

MUMS designation is modeled on the ODD for human drug development and offers possible financial incentives to encourage MUMS drug development, such as the availability of grants to help with the cost of developing the MUMS drug.

Canalevia is also the Company’s drug candidate for the proposed indication of exercise-induced diarrhea (“EID”) in dogs.

Crofelemer is extracted and purified from the Croton lechleri tree, which we sustainably harvest and manage through programs that we have been developing over the past 30 years.

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Additionally, through the establishment of a nonprofit called the Healing Forest Conservancy, our team has created a long-term mechanism for benefit sharing that recognizes the intellectual contribution of Indigenous populations.

This program is intended to contribute to the continued strength and effectiveness of the valued and strategically important relationships we have carefully cultivated over the past 30+ years.

This program is intended to contribute to the continued strength and effectiveness of the valued and strategically important relationships we have carefully cultivated over the past more than 30 years.

Product Pipeline

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FDA for the symptomatic relief of noninfectious diarrhea in adults with HIV/AIDS on antiretroviral therapy, we are also developing a pipeline of prescription drug product candidates to address unmet needs in gastrointestinal health through Napo.

Mytesi (crofelemer) is a novel, first in class anti secretory agent which has a basic normalizing effect locally in the gut and lumen, and this mechanism of action has the potential to benefit multiple disorders.

Mytesi (crofelemer) is a novel, first-in-class anti-secretory antidiarrheal drug which has a normalizing effect to restore the electrolyte and fluid balance in the gut and lumen, and this mechanism of action has the potential to benefit multiple disorders.

Clinical trials demonstrated that nearly 80% of Mytesi users experienced an improvement in their diarrhea over a four-week period.

At week 20 of the pivotal trial, over half the patients had no watery stools, or a 100% decrease, and 83% had at least a 50% decrease in watery stools.

Our Mytesi pipeline currently includes prescription drug product candidates for four follow on indications, several of which are backed by Phase 2 evidence from completed Phase 2 trials.

In addition, a second generation proprietary anti secretory agent, lechlemer, is in development for cholera-related diarrhea.

Our Mytesi pipeline currently includes prescription drug product candidates for multiple follow-on indications, several of which are backed by Phase 2 evidence from clinical trials.

In addition, NP-300 is in development for symptomatic relief and treatment of moderate-to-severe diarrhea, with or without concomitant antimicrobial therapy, from bacterial, viral and parasitic infections including Vibrio cholerae , the bacterium that causes cholera.

Napo Prescription Drug Product Candidates

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Initiated pivotal Phase 3 clinical trial in October 2020

Findings of Phase 2 HALT-D study presented in Q4 2021

Enrollment in Phase 3 trial ongoing

Novel lyophilized crofelemer product

Rare disease indications (SBS & CDD)

Orphan drug designation for SBS granted by FDA and EMA

Initiate Phase 2 proof of concept (POC) study in SBS and/or CDD in 2022

Target trial enrollment of 256 patients expected to complete in Q2 2023

Two Phase 2 studies completed

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Chronic idiopathic diarrhea

Initiated clinical study at The University of Texas Health Science Center at Houston (“UTH”)

Top line results of UTH trial expected in 2022

Clinical POC study initiated at The University of Texas Health Science Center at Houston (“UTH”)

Phase 2 POC study

Top line results expected in 2023

Functional diarrhea

Initiated clinical study at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston

Phase 2 POC study

Enrollment ongoing

Safety evidence from other chronic diarrhea indications

KOL discussions ongoing

NP-300 (lechlemer)

Second-generation antidiarrheal drug for infectious diarrhea including from cholera

Ongoing IND-enabling toxicology studies and formulation development

Initiate Phase 1 trial in the second half of 2022

powder for oral solution*

Rare disease indication:

SBS with intestinal failure in adults

ODD for SBS granted by FDA and EMA

Clinical POC study

IIT POC study in 2023

Crofelemer powder for oral solution*

Rare disease indication:

Pediatric MVID, a CDD condition

ODD for MVID granted by FDA and EMA

Initiate clinical study in 2023

Second-generation antidiarrheal drug for infectious diarrhea including from Vibrio cholerae , the bacterium that causes cholera

FDA activated Company’s IND:

Initiating Phase 1 trial

*Clinical trials are funding dependent

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According to data from the U.S.

Centers for Disease Control and Prevention, by 2020 more than 70% of Americans with HIV are expected to be 50 and older and have lived with HIV for more than 10 years (1).

Centers for Disease Control and Prevention, it was estimated that by 2020 more than 70% of Americans with HIV were 50 and older and had lived with HIV for more than 10 years (1).

Market Size/Potential

HIV-related Diarrhea

HIV-related Diarrhea (Mytesi)

We estimate the U.S.

market revenue potential for Mytesi to be approximately $50 million in gross annual sales.

CTD (Crofelemer delayed-release tablets)

An estimated 650,000 U.S.

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Global CINV market projected to reach a valuation of $2.7 billion by 2022(4).

Financial benefits of Orphan Drug Designation.

SBS/CDD (Crofelemer powder for oral solution)

Financial benefits of ODD.

The global SBS market exceeded $568 million in 2019 and is expected to reach $4.6 billion by 2027, according to a report by Vision Research Reports(5).

IBS-D (Crofelemer delayed-release tablets)

Most IBS products have an estimated revenue potential of greater than $1.0 billion(6).

Estimated 1,171,000 Americans have IBD(7)

Infectious Diarrhea from Cholera

In recent transactions by other companies, priority review vouchers have sold for $67 million to $350 million(8)

Infectious Diarrhea (NP-300 tablets)

In transactions by other companies, priority review vouchers have sold for $67 million to $350 million(7).

HIV Among People Aged 50 and Older (https://www.cdc.gov/hiv/group/age/olderamericans/index.html)

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Rodman & Renshaw estimate peak annual sales of Synergy Pharmaceuticals’ Trulance at $2.3 bn in 2021 (https://www.benzinga.com/analyst-ratings/analyst-color/17/04/9304883/what-synergys-new-patents-mean-for-its-commercial-prospe)

Kappelman, M.

Recent Trends in the Prevalence of Crohn’s Disease and Ulcerative Colitis in a Commercially Insured US Population.

2015, AbbVie Inc.

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(https://investors.biomarin.com/2014-07-30-BioMarin-Sells-Priority-Review-Voucher-for-67-5-Million).

The following diagram illustrates the mechanism of action of our human and animal gastrointestinal drug products and drug product candidates, which normalize chloride and water flow and transit time of fluids within the intestinal lumen.

The following diagram illustrates the mechanism of action of crofelemer, which normalizes chloride ion secretion and fluid content of the gut to improve stool consistency.

Business Strategy

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Expand Mytesi by leveraging our significant gastrointestinal product knowledge, experience and intellectual property portfolio

Mytesi is a novel, first in class anti secretory antidiarrheal agent which has a basic normalizing effect locally on the gut, and this mechanism of action has the potential to benefit multiple gastrointestinal disorders.

Mytesi (crofelemer 125 mg delayed-release tablets) is a novel, first-in-class anti-secretory antidiarrheal agent which has a normalizing effect on the electrolyte and fluid balance in the gut, and this mechanism of action has the potential to benefit multiple gastrointestinal disorders.

Our Mytesi (crofelemer) product is approved by the U.S.

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Jaguar, through Napo, holds global unencumbered rights for Mytesi.

Mytesi is in development for multiple possible follow on indications, including diarrhea related to targeted cancer therapy;

orphan drug indications for infants and children with congenital diarrheal disorders and short bowel syndrome;

inflammatory bowel disease;

irritable bowel syndrome;

and for idiopathic/functional diarrhea.

In addition, a second generation proprietary anti secretory agent is in development for cholera.

Mytesi is in development for multiple possible follow-on indications, including prophylaxis of diarrhea related to targeted therapy with or without standard chemotherapy.

Crofelemer delayed-release tablets are also being evaluated in IBS-D and idiopathic/functional diarrhea.

Crofelemer powder for oral solution is being developed to support orphan or rare disease indications for infants and/or children with SBS and/or CDD, such as MVID.

In addition, a NP-300 is in development for symptomatic relief and treatment of moderate-to-severe diarrhea, with or without concomitant antimicrobial therapy, from bacterial, viral and parasitic infections including Vibrio cholerae , the bacterium that causes cholera.

Our management team collectively has extensive experience in the development of prescription drugs.

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Maintain commercial capabilities in Mytesi sales and marketing efforts

Napo’s direct sales organization is comprised of Mytesi field sales representatives strategically positioned to cover U.S.

Napo’s direct sales organization is comprised of Mytesi field sales representatives strategically positioned in different territories to cover U.S.

geographies with the highest potential.

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Leverage our relationships with Scientific Advisory Board (SAB) members for crofelemer commercialization and development in follow-on indications

The Company has retained 10 SAB members that have extensive clinical experience in HIV, CTD, IBD, SBS, and CDD.

In addition, the Company engages key opinion leaders (KOLs) for specific turnkey needs.

The Company has retained several subject matter experts and KOLS as its SAB members across the therapeutic areas of HIV, CTD, gastrointestinal disorders, SBS, and/or CDD.

Establish partnerships to support moving pipeline indications to pivotal clinical trials

Jaguar is actively pursuing the development of a robust pipeline of potential follow on indications for crofelemer, and the Company’s goal is to establish partnerships to support moving pipeline indications to pivotal clinical trials.

The Company’s goal is to establish partnerships to support moving pipeline indications towards commercialization in the US and/or other geographies.

Strategically sequence the development of follow-on indications of Mytesi and seek geographically focused licensing opportunities

As announced April 1, 2022, the Company has entered an agreement with Quadri Pharmaceuticals Store LLC (Quadri Pharma) that grants Quadri Pharma exclusive promotional, commercialization, and distribution rights for specified human indications of Mytesi (crofelemer 125 mg delayed-release tablets) in Bahrain, Kuwait, Qatar, Saudi Arabia, the United Arab Emirates (UAE), and Oman following regulatory approval to market crofelemer in these countries for the specified indications, including the indication currently approved in the U.S.

for HIV-related diarrhea.

They also have rights to commercialization, for Mytesi for CTD, for which crofelemer is currently in a pivotal Phase 3 clinical trial.

In addition, the agreement grants Quadri Pharma exclusive rights to distribute crofelemer in these countries in the immediate future under Named Patient Programs.

As announced September 24, 2018, Jaguar and Knight Therapeutics Inc.

(“Knight”) entered into a Distribution, License and Supply Agreement that grants Knight the exclusive right to commercialize Mytesi and related products in Canada and Israel.

The License Agreement has a term of 15 years (with automatic renewals) and provides Knight with an exclusive right to commercialize current and future Jaguar human health products (including crofelemer, Lechlemer, and any product containing a proanthocyanidin or with an anti-secretory mechanism) in Canada and Israel.

The License Agreement has a term of 15 years (with automatic renewals) and provides Knight with an exclusive right to commercialize current and future Jaguar human health products (including crofelemer, NP-300, and any product containing a proanthocyanidin or with an anti-secretory mechanism) in Canada and Israel.

Knight forfeited its right of first negotiation for expansion to Latin America.

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Reduce risks relating to product development

Risk reduction is a key focus of our product development planning.

Mytesi is approved for chronic indication, providing us the ability to leverage this corresponding safety data when seeking approval for planned follow on indications that are also chronic or chronic episodic indications.

Risk reduction is a key focus of our product development programs.

Mytesi is FDA approved for a first-in-class chronic noninfectious diarrhea indication in adult HIV/AIDS patients receiving antiretroviral therapy (“ART”).

This FDA approved New Drug Application (“NDA”) provides, us the ability to leverage this corresponding safety data when seeking approval for additional follow-on indications that are also chronic or chronic episodic indications.

In an effort to reduce risk further, we have implemented the following approach:

first, we meet with key opinion leaders, typically at medical conferences.

Next, we confirm unmet medical needs with these key opinion leaders and discuss the practicality of patient enrollment and trial implementation.

first, we meet with KOLs, including at medical conferences.

Next, we confirm unmet medical needs with patients as well as KOLs and discuss the practicality of patient enrollment and trial implementation.

We then generate protocols to discuss with the FDA, seeking, when possible, special protocol assessments.

Our goal is to have de risked the program as much as we believe we possibly can, by the time we start devoting significant funds to a clinical trial, in particular the regulatory pathway.

Our goal is to have de risked the program as much as we believe

we possibly can, by the time we start devoting significant funds to a clinical trial, in particular the regulatory pathway.

We believe this approach will lead to better long-term outcomes for our products in development.

We will continue to seek partnerships outside the United States for the above indications while focusing on development and commercial access in the United States directly.

We are also focused on investigating (lechlemer) for various gastrointestinal indications.

Lechlemer is a proprietary Jaguar pharmaceutical product, a standardized botanical extract distinct from crofelemer, also sustainably derived from the Croton lechleri tree.

We believe lechlemer, which has a similar mechanism of action as crofelemer and is significantly less costly to produce, may support efforts to receive a priority review voucher from the U.S.

FDA for symptomatic treatment of diarrhea from cholera infection.

We are also focused on investigating NP-300 for various gastrointestinal indications.

NP-300 is a proprietary Jaguar pharmaceutical product, a standardized botanical extract distinct from crofelemer, also sustainably derived from the Croton lechleri tree.

We believe NP-300, which has a similar mechanism of action as crofelemer and is significantly less costly to produce, may support efforts to receive a priority review voucher from the U.S.

FDA for symptomatic relief and treatment of moderate-to-severe diarrhea, with or without concomitant antimicrobial therapy, from bacterial, viral and parasitic infections including Vibrio cholerae , the bacterium that causes cholera.

Priority review vouchers are granted by the FDA to drug developers for tropical disease indications (TDPRV) as an incentive to develop treatments for neglected diseases and rare pediatric diseases.

Additionally, we believe lechlemer represents a long-term pipeline opportunity as a second generation anti secretory agent, on a global basis, for multiple gastrointestinal diseases—especially in resource constrained countries where the cost of goods is a factor, in part, because requirements often exist in such regions for drug prices to decrease annually.

Additionally, we believe NP-300 represents a long-term pipeline opportunity as a second-generation anti-secretory agent, on a global basis, for multiple gastrointestinal diseases—especially in resource constrained countries where the cost of goods is a factor, in part, because requirements often exist in such regions for drug prices to decrease annually.

The Company has previously presented Phase 2 data on crofelemer for the treatment of diarrhea in cholera patients from a study in Bangladesh.

Napo plans to follow a similar clinical study design to support the development of lechlemer (NP-300) for a cholera related indication.

Napo is conducting IND-enabling preclinical toxicology studies and developing novel NP-300 formulations that will support the initiation of clinical studies in 2022.

Napo plans to follow a similar clinical study design to support the development of NP-300 for a cholera-related indication.

Our portfolio development strategy is based on identifying indications that are potentially high value because they address important medical needs that are significantly or globally unmet, and then strategically sequencing indication development priorities, second-generation product pipeline development, and partnering goals on a global basis.

Our technology for proprietary gastrointestinal disease products is central to the product pipelines of both human and veterinary indications.

Crofelemer is also the API in Canalevia-CA1, our prescription drug product recently conditionally approved by the FDA and launched for CID in dogs, and also expected to be approved and launched, under the name Canalevia-CA2, for EID in dogs in the fourth quarter of 2022.

Napo Therapeutics Provides New Opportunities to Treat Orphan Indications Like Short Bowel Syndrome

Crofelemer is also the active pharmaceutical ingredient (“API”) in Canalevia-CA1, our prescription drug product conditionally approved by the FDA and launched for CID in dogs.

Napo Therapeutics Provides New Opportunities to Treat Orphan Indications Like SBS

Jaguar is strategically pursuing multiple important shots on goal for its drug development pipeline:

Crofelemer for CTD, led by Napo, and crofelemer for SBS and CDD, led by Napo Therapeutics.

Jaguar’s exclusive license agreement with Napo Therapeutics provides a perpetual, royalty-bearing license for Europe (excluding Russia), and includes traditional terms such as up-front fees, milestone payments, royalties on sales in Europe, and a supply agreement, and rights to utilized all data Napo Therapeutics generates for Jaguar development and approval activities globally.

Jaguar’s exclusive license agreement with Napo Therapeutics provides a perpetual, royalty-bearing license for Europe, and includes traditional terms such as royalties on sales in Europe, and a supply agreement, and rights to utilize all data Napo Therapeutics generates for Jaguar development and approval activities globally.

There are several significantly larger pharmaceutical companies competing with us in the gastrointestinal segment.

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Cancer therapy related diarrhea.

We are not aware of any FDA approved drugs specifically indicated for cancer therapy related diarrhea, including chemotherapy related diarrhea.

A recent Phase 2b trial of elsiglutide for the treatment of chemotherapy induced diarrhea in colorectal cancer patients did not meet statistical significance.

We are not aware of any FDA approved drugs specifically indicated for prophylaxis of cancer therapy related diarrhea in patients receiving targeted therapies with or without standard chemotherapy.

Opioids and over-the-counter drugs are commonly used to treat chemotherapy induced diarrhea, but these drugs affect motility.

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For example, FDA guidance suggests diarrhea prophylaxis prior to initiating adjuvant therapy with neratinib.

Short Bowel Syndrome and Congenital Diarrheal Disorders .

We are not aware of any FDA approved drugs specifically indicated for congenital diarrheal disorders.

In the U.S., Takeda Pharmaceuticals’ GATTEX® (teduglutide) is indicated for the treatment of adults and pediatric patients 1 year of age and older with short bowel syndrome who are dependent on parenteral support, and Zorbtive® is a recombinant human growth hormone indicated for the treatment of short bowel syndrome in adult patients receiving specialized nutritional support.

We are not aware of any FDA approved drugs specifically indicated for CDD.

SBS with intestinal failure.

In the U.S., Takeda Pharmaceuticals’ GATTEX ® (teduglutide) is indicated for the treatment of adults and pediatric patients 1 year of age and older with SBS who are dependent on parenteral support.

Zorbtive ® is a recombinant human growth hormone indicated for the treatment of SBS in adult patients receiving specialized nutritional support.

To the best of our knowledge, no drugs have been approved in the US or rest of the world (ROW) for the reduction of parenteral support with a concomitant reduction in the high stool volume and diarrhea in SBS patients.

Diarrhea predominant irritable bowel syndrome .

Two drugs were approved in 2015 for the treatment of diarrhea predominant irritable bowel syndrome, Allergan plc’s Virbezi and Xifaxan, which is marketed by Valeant Pharmaceuticals International.

Two drugs were approved in 2015 for the treatment of diarrhea predominant irritable bowel syndrome, Allergan plc’s Viberzi and Xifaxan, which is marketed by Valeant Pharmaceuticals International.

Also, Lotronex was approved by the FDA in 2000 but was withdrawn from the market and later reintroduced in 2002 under a Risk Management Program.

With the exception of Lotronex, the sponsors of

Verbezi and Xifaxan employ extensive media and print promotion for the commercialization of these products.

We are seeking a partner to further the clinical development and commercialization of crofelemer for IBS-D.

There are currently numerous trials ongoing for IBS-D.

Inflammatory Bowel Disorders.

We are not aware of any FDA approved drugs specifically indicated as an anti-secretory agent for use to address IBD.

Infectious Diarrhea from Cholera .

We are not aware of any FDA approved drugs specifically indicated as an anti-secretory agent for use to address the devastating dehydration in cholera patients.

With the exception of Lotronex, the sponsors of Viberzi and Xifaxan employ extensive media and print promotion for the commercialization of these products.

Infectious diarrhea .

We are not aware of any FDA approved drugs specifically acting as anti-secretory drugs to improve stool consistency.

Oral rehydration solution (ORS) with or without the use of antibiotics is the current standard of care for infectious diarrhea.

NP-300 provides a first of its kind antisecretory antidiarrheal drug which would potentially reduce the duration of diarrhea including its sequalae such as hospitalization.

Manufacturing

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(“Indena”), a Milan, Italy based contract manufacturer dedicated to the identification, development and production of high-quality active principles derived from plants, for use in the pharmaceutical, health food and personal care industries.

Indena has completed the required technology transfer and feasibility and preparing for validation activities to support commercial scale manufacturing.

We have contracts in place with all the manufacturers and third-party testing labs required to manufacture Mytesi, Canalevia-CA1, and lechlemer.

We are finalizing a master service agreement with Indena for the manufacture of crofelemer.

We are evaluating alternate drug substance and drug product manufacturers to establish redundancy for DP manufacturing.

Indena has completed the required validation activities to gain approval as a manufacturer of crofelemer drug substance.

As announced January 25, 2023, the required procedure of registering the source of the API of crofelemer with the Agenzia Italiana Del Farmaco (“AIFA”), the Italian Medicines Agency, has been successfully completed.

Resultingly, batches of crofelemer API manufactured by Indena can now be used by Jaguar for further development work.

This was a key milestone in the ongoing process of establishing Indena as an additional approved crofelemer manufacturer as we work to support the increased crofelemer manufacturing demand expected upon potential FDA approval of crofelemer for new indications, including approval for CTD.

Proprietary Library of Medicinal Plants

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or Calophyllum spp., including Mytesi (crofelemer).

The patent family associated with International Patent publication WO1998/16111 relates to enteric protected formulations

of proanthocyanidin polymers isolated from Croton spp.

or Calophyllum spp., including crofelemer, and methods of treating watery diarrhea using these enteric protected formulations.

There is one U.S.

patent in force in this family, US 7,341,744, which has a term until at least June 23, 2019, which term has been extended under 35 U.S.C.

156 by 1,075 days.

Based upon the June 23, 2019 expiration date, the expiration date for crofelemer is June 2, 2022, to account for the regulatory delay in obtaining human marketing approval for crofelemer.

Napo additionally owns a family of patents arising from International Patent Application Publication WO2012/058664 that cover methods of treating HIV associated diarrhea and HAART associated diarrhea with proanthocyanidin polymers isolated from Croton spp.

Napo owns a family of patents arising from International Patent Application Publication WO2012/058664 that cover methods of treating HIV associated diarrhea and HAART associated diarrhea with proanthocyanidin polymers isolated from Croton spp.

or Calophyllum spp., including crofelemer.

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In particular, for diarrhea predominant irritable bowel syndrome, Napo has two issued U.S.

patents, US 8,846,113 and US 9,980,938, which expire on February 9, 2027, as well as issued patents in Australia, Canada, Europe, Gulf States, Hong Kong, Japan, South Korea, Mexico, New Zealand, Singapore, and Taiwan and pending applications in Bangladesh, Bolivia, Chile, Paraguay, Thailand, and Venezuela, all of which are estimated to expire April 30, 2027;

patents, US 8,846,113 and US 9,980,938, which expire on February 9, 2027, as well as issued patents in Australia, Canada, Europe, Gulf States, Hong Kong, Japan, South Korea, Mexico, New Zealand, Singapore, Thailand, and Taiwan and pending applications in Bangladesh, and Venezuela, all of which are estimated to expire April 30, 2027;

for constipation predominant irritable bowel syndrome, Napo has three issued U.S.

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patents, US 8,852,649 and US 9,987,250 with terms until at least January 4, 2028, as well as issued patents in Australia, Hong Kong, and Europe and Canada, which have estimated expiration dates of April 30, 2027.

Napo has a pending U.S.

non provisional application for the treatment of CID with crofelemer filed on March 9, 2018, as well as International and Taiwanese applications, and two International Patent Applications on other human indications including for the treatments of short bowel syndrome and congenital diarrhea disorder filed on May 31, 2018, with pending national phase applications in the United States, Australia, Canada, China, Europe, Israel, Jordan, Japan and the Gulf States.

Napo has a U.S.

patent for the treatment of CID caused by neratinib with crofelemer and a related continuation application also directed to treating CID effectively filed on March 9, 2018, as well as multiple pending national stage applications outside the US also directed to treating CID with crofelemer effectively filed June 19, 2020.

In addition, Napo has two patent families each with pending applications in United States, Australia, Canada, China, Europe, Israel, Jordan, Japan and the Gulf States directed to the treatments of SBS and CDD, respectively, and each filed on May 31, 2018.

Napo also has pending International applications to “Methods and Compositions For Treating Post-Acute Infection Gastrointestinal Disorders” filed November 23, 2021.

For methods of manufacturing proanthocyanidin polymers isolated from Croton spp.

or Calophyllum spp., including crofelemer, Napo owns issued patents in India, South Africa, and Eurasia with terms at least until August 26, 2029.

Napo also owns issued patents in Brazil, India, Russia, and South Africa and pending applications in Argentina and Venezuela that also cover methods of manufacturing proanthocyanidin polymers isolated from Croton spp.

Napo also owns issued patents in Brazil, India, and Russia, and a pending application in Venezuela that also cover methods of manufacturing proanthocyanidin polymers isolated from Croton spp.

or Calophyllum spp., including crofelemer, with terms at least until January 17, 2032.

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patents covering a formulation of NP 500 (nordihydroguiaretic acid (“NDGA”)) and its use in treating a metabolic disorder that have terms until April 23, 2031.

Napo grants license to Napo Therapeutics S.p.A.

(formerly named Napo EU S.p.A.)

On August 2021, Napo signed a license agreement with Napo EU S.p.A.

The license agreement grants Napo Thera the rights for SBS-IF, HIV-related diarrhea, and the symptomatic relief and treatment of IF-related diarrhea in patients with congenital disorders.

The license agreement grants Napo Thera the right to study Per the terms of the license agreement, Napo will receive payment of up to $10 million as the initial license fee (to be paid in two installments, the first of which has already been received) as the initial license fee and is eligible to receive additional payments related to milestones, royalties, and product transfers.

The license fees will be eliminated in the consolidated financial statements.

Napo also has two international applications pending directed to alstonine derivatives and salts thereof and uses thereof for treating psychotic disorders which were filed on June 14, 2022, and October 26, 2022, respectively.

Napo grants license to Napo Therapeutics

On August 2021, Napo signed a license agreement with Napo Therapeutics to study, develop, manufacture, and commercialize Napo’s plant-based crofelemer and NP-300 drug product candidates in the European Union (excluding Russia) and in specified non-EU countries in Europe for specific indications, which rights and obligations were assumed by the combined company formed by the merger of Napo EU S.p.A.

with Dragon SPAC (the combined company uses the Napo Therapeutics name).

The license agreement grants Napo Therapeutics the rights for SBS-IF, HIV-related diarrhea, and the symptomatic relief and treatment of IF-related diarrhea in patients with congenital disorders.

Government Regulation

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Government Regulation

Human Prescription Drugs

In the United States, the FDA approves and regulates drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”), and it’s implementing regulations.

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requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending New Drug Applications (“NDAs”), withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

The process required by the FDA before a human or animal health prescription drug may be marketed in the United States generally involves the following:

The process required by the FDA before a human prescription drug may be marketed in the United States generally involves the following:

● completion of pre-clinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or good laboratory practices (“GLPs”) regulations;

● submission to the FDA of an investigational new drug application (“IND”) for human clinical trials, or an investigational new animal drug (“INAD”) for animal health studies;

● approval by an institutional review board (“IRB”) for human trials, and appropriate animal care and use committees for animal health studies.

● submission to the FDA of an investigational new drug application (“IND”) for human clinical trials;

● approval by an institutional review board (“IRB”) for human trials.

Multiple sites may necessitate the involvement of multiple IRBs and submissions for human health products;

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● submission to the FDA of an NDA for marketing approval of human prescription drugs;

and a new animal drug application (“NADA”) for marketing authorization of animal health products;

● satisfactory completion of FDA advisory committees review, if applicable;

● satisfactory completion of an FDA pre-approval inspection (“PAI”) of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMPs”), requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

● FDA review and approval of the NDA or NADA.

● FDA review and approval of the NDA.

Pre-clinical Studies

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Special Protocol Assessment for Human Health Prescription Drugs

clinical trials that can form the primary basis for a drug product’s efficacy claim in an NDA.

The special protocol assessment, or SPA, process is designed to facilitate the FDA’s review and approval of drugs by allowing the FDA to evaluate issues related to the adequacy of certain clinical trials, including Phase 3 clinical trials that can form the primary basis for a drug product’s efficacy claim in an NDA.

Upon specific request by a clinical trial sponsor, the FDA will evaluate the protocol and respond to a sponsor’s questions regarding, among other things, primary efficacy endpoints, trial conduct and data analysis, within 45 days of receipt of the request.

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The FDA may request additional information rather than accept an NDA for filing.

In this event, the application must be

resubmitted with the additional information.

In this event, the application must be resubmitted with the additional information.

The resubmitted application is also subject to review before the FDA accepts it for filing.

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Post-Approval Requirements for Human Prescription Drugs

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.

product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product.

After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval.

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Products, if deemed adulterated, can lead to serious consequences as set forth above as well as civil and criminal penalties.

Animal Health Prescription Drugs

Under the Federal Food, Drug, and Cosmetic Act (the “Act”), the term "drug"

means articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary;

articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;

and articles other than food intended to affect the structure or any function of the body of man or other animals.

It also includes articles intended for use as a component of a drug.

Once a product is determined to be a drug for animal use, the next step is to determine whether or not it is a new animal drug.

The Act defines a new animal drug (in part) as any drug intended for use for animals other than man, the composition of which is not generally recognized, among experts qualified by scientific training and experience, as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling.

By virtue of Supreme Court interpretations of the necessary basis for general recognition, there are, for all practical purposes, no animal drugs which are not also new animal drugs.

Under the Act, a new animal drug may not be legally introduced into interstate commerce unless it is the subject of either:

● an approved NADA or abbreviated new animal drug application (ANADA) under section 512 of the Act;

● a conditional approval under section 571 of the Act;

● a listing on the Legally Marketed Unapproved New Animal Drug Index for Minor Species (the Index) under section 572 of the Act;

● an emergency use authorization (“EUA”) under section 564 of the Act (an EUA may only be issued under very limited circumstances, more information regarding EUAs is available at this webpage:

Emergency Use Authorization) ;

● an investigational exemption under section 512(j) of the Act.

Three Regulatory Pathways in the U.S.

to Legal Marketing Status for Animal Health Drugs

An approved animal drug has gone through the New Animal Drug Application (NADA) process, or for an approved generic animal drug, the Abbreviated New Animal Drug Application (ANADA) process.

If the information in the application meets the requirements for approval, FDA approves the animal drug.

FDA’s approval means the drug is safe and effective when it is used according to the label.

FDA’s approval also ensures that the drug’s strength, quality, and purity are consistent from batch to batch, and that the drug’s labeling is truthful, complete, and not misleading.

Conditional Approval

Conditional approval is only available for some animal drugs for use in a minor species or in a major species under special circumstances.

A conditionally approved animal drug has gone through FDA's drug approval process except the drug has not yet met the effectiveness standard for full approval.

FDA’s conditional approval means that when used according to the label, the drug is safe and has a “reasonable expectation of effectiveness.” FDA's conditional approval also means that the drug is properly manufactured.

The conditional approval is valid for one year.

The drug company can ask FDA to renew the conditional approval annually for up to four more years, for a total of five years of conditional approval.

During the 5-year period, the drug company can legally sell the animal drug while collecting the remaining effectiveness data.

After collecting the remaining effectiveness data, the company submits an application to FDA for full approval.

The agency reviews the application and, if appropriate, fully approves the drug.

An indexed animal drug is a drug on FDA’s Index of Legally Marketed Unapproved New Animal Drugs for Minor Species, referred to simply as “the Index.” As the name says, a drug listed on the Index is unapproved but has legal marketing status.

It can be legally sold for a specific use in certain minor species.

Indexing is allowed for drugs for:

● Non-food-producing minor species, such as pet birds, hamsters, and ornamental fish.

These animals are typically not eaten by people or by other animals that produce food for people to eat;

● An early non-food life stage of a food-producing minor species, such as oyster spat (immature oysters).

Because people do not generally eat oyster spat, a drug to treat a disease in spat can be indexed, but a drug to treat a disease in adult oysters, which people commonly eat, cannot be indexed.

Indexing a drug is quite different from the drug approval process.

Indexing relies heavily on a panel of qualified experts outside FDA.

The experts review the drug’s safety in the specific minor species and the drug’s effectiveness for the intended use.

All experts on the panel must agree that, when used according to the label, the drug’s benefits outweigh the risks to the treated animal.

If FDA agrees with the panel, the agency adds the drug to the Index.

Animal Health Business Regulations

The development, approval and sale of animal health products are governed by the laws and regulations of each country in which we intend to seek approval, where necessary, to market and subsequently sell our prescription drug and non-drug products.

To comply with these regulatory requirements, we have established processes and resources to provide oversight of the development, approval processes and launch of our products and to position those products in order to gain market share in each respective market.

federal regulatory agencies are charged with oversight and regulatory authority of animal health products in the United States.

These agencies, depending on the product and its intended use, may include the FDA, the USDA and the Environmental Protection Agency.

The approval of prescription drugs intended for animal use is regulated by the FDA’s CVM.

In addition, the Drug Enforcement Administration regulates animal therapeutics that are classified as controlled substances.

In addition, the Federal Trade Commission may, in the case of non-drug products, regulate the marketing and advertising claims being made.

The FDA plays a significant role in regulating the labeling, advertising and promotion of animal drugs.

This is also true of regulatory agencies in the EU and other territories.

In addition, advertising and promotion of animal health products is controlled by regulations in many countries.

These rules generally restrict advertising and promotion to those claims and uses that have been reviewed and approved by the applicable agency.

We will conduct a review of advertising and promotional material for compliance with the local and regional requirements in the markets where we sell our product candidates.

EMA Regulation of Human Prescription Drugs

Napo and Napo Therapeutics intend to leverage the orphan medicines marketing authorization incentives from the EMA for the short bowel syndrome and congenital diarrheal disorders indications for crofelemer for the licensed territories in the European Union.

Napo and Napo Therapeutics intend to leverage the orphan medicines marketing authorization incentives from the EMA for the SBS and CDD indications for crofelemer for the licensed territories in the European Union.

EMA has developed a regulatory procedure for sponsor eligibility for incentives available for drugs with ODD for the appropriate patient populations in an expedited manner.

The EMA is responsible for scientific evaluation of centralized marketing authorization applications (“MAA”).

The EMA is responsible for scientific evaluation of

centralized marketing authorization applications (“MAA”).

Once granted by the European Commission, the centralized MAA is valid in all EU member states, Iceland, Norway and Liechtenstein.

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Guidance for applicants for conditional marketing authorization

EMA advises applicants to discuss their development plans with the Agency via scientific advice or protocol assistance early in the development process.

EMA advises applicants to discuss their development plans with the EMA via scientific advice or protocol assistance early in the development process.

Involving health technology assessment bodies early is also encouraged, which is possible via EMA's parallel consultations procedure.

The applicant should indicate a request for conditional marketing authorization in their notification of intention to submit a marketing authorization application.

They should submit this 6 to 7 month before submitting the application.

They should submit this six to seven months before submitting the application.

EMA also encourages applicants to further discuss their plans with EMA as part of a pre-submission meeting.

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Protocol assistance

The Agency provides a form of scientific advice specifically for orphan medicines called protocol assistance.

The EMA provides a form of scientific advice specifically for orphan medicines called protocol assistance.

This allows sponsors to get answers to their questions on the types of studies needed to demonstrate the medicine's quality, benefits and risks, and information on the significant benefit of the medicine.

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There is no restriction on the number of times a sponsor can request protocol assistance.

The Agency encourages sponsors to consider coordinating the timing of protocol assistance from the Agency with request for scientific advice from the United States Food and Drug Administration (FDA).

The EMA encourages sponsors to consider coordinating the timing of protocol assistance from the EMA with request for scientific advice from the FDA.

Parallel scientific advice with the FDA is available.

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All designated orphan medicines are assessed for marketing authorization centrally in the European Union.

This allows companies to make a single application to the European Medicines Agency, resulting in a single opinion and a single decision from the European Commission, valid in all EU Member States.

This allows companies to make a single application to the EMA, resulting in a single opinion and a single decision from the European Commission, valid in all EU Member States.

Sponsors may also have access via orphan designation to conditional approval, which is conducted under the centralized procedure.

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Authorized orphan medicines benefit from ten years of protection from market competition with similar medicines with similar indications once they are approved.

This period of protection is extended by two years for

medicines that also have complied with an agreed pediatric investigation plan granted at the time of review of the orphan medicine designation.

This period of protection is extended by two years for medicines that also have complied with an agreed pediatric investigation plan granted at the time of review of the orphan medicine designation.

Additional incentives for micro, small and medium-sized enterprises (“SMEs”)

Companies classified as SMEs benefit from further incentives when developing medicines with orphan designation.

These include administrative and procedural assistance from the Agency's SME office and fee reductions.

These include administrative and procedural assistance from the EMA’s SME office and fee reductions.

Fee reductions

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Fee reductions are revised each year in relation to the budget available.

The Agency does not offer research grants for sponsors of orphan medicines, but funding is available from the European Commission and other sources:

The EMA does not offer research grants for sponsors of orphan medicines, but funding is available from the European Commission and other sources:

● Horizon 2020, the EU Framework Programme for Research and Innovation;

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For information and guidance on using IRIS, see the IRIS homepage.

Sponsors must submit an annual report on development to the Agency summarizing the status of development of the medicine.

Sponsors must submit an annual report on development to the EMA summarizing the status of development of the medicine.

Sponsors of medicines with orphan designation should also remember to apply for a pediatric investigation plan (“PIP”), deferral or waiver at the appropriate time, as specified in the Pediatric regulation.

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The CHMP also identifies which patients would benefit, and Member States should take note of these recommendations when making decisions.

Manufacturers and marketing-authorization applicants should not contact EMA to request an opinion, but they may wish to inform the Agency of applications underway at national level.

National competent authorities will inform the Agency if they are making a product available to a group of patients for compassionate use.

Manufacturers and marketing-authorization applicants should not contact EMA to request an opinion, but they may wish to inform the EMA of applications underway at national level.

National competent authorities will inform the EMA if they are making a product available to a group of patients for compassionate use.

Comparison to individual basis treatment (Named Patient Program)

Compassionate use should not be confused with 'named-patient basis' treatments, which see doctors obtain medicines directly from manufacturers before authorization.

This is done on an individual basis under the direct responsibility of the doctor, and the Agency does not need to be informed.

This is done on an individual basis under the direct responsibility of the doctor, and the EMA does not need to be informed.

In general, medicines that are not yet authorized are first made available through clinical trials and patients should always be considered for inclusion in trials before being offered compassionate use programs.

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Several rewards and incentives for the development of pediatric medicines for children are available in the EU.

Medicines authorized across the EU with the results of studies from a pediatric investigation plan included in the

product information are eligible for an extension of their supplementary protection certificate by six months.

Medicines authorized across the EU with the results of studies from a pediatric investigation plan included in the product information are eligible for an extension of their supplementary protection certificate by six months.

This is the case even when the studies' results are negative.

For orphan medicines, the incentive is an additional two years of market exclusivity.

Scientific advice and protocol assistance at the Agency are free of charge for questions relating to the development of pediatric medicines.

Scientific advice and protocol assistance at the EMA are free of charge for questions relating to the development of pediatric medicines.

Medicines developed specifically for children that are already authorized but are not protected by a patent or supplementary protection certificate are eligible for a pediatric-use marketing authorization (“PUMA”).

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In the EU, new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a

generic application for eight years, after which a generic marketing authorization application can be submitted, and the innovator’s data may be referenced, but not approved for two years.

This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic application for eight years, after which a generic marketing authorization application can be submitted, and the innovator’s data may be referenced, but not approved for two years.

The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

European Union orphan designation and exclusivity

In the EU, the EMA’s Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons in the European Union Community and for which no satisfactory method of diagnosis, prevention, or treatment has been authorized (or the product would be a significant benefit to those affected).

In the EU, the EMA’s Committee for Orphan Medicinal Products grants ODD to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than 5 in 10,000 persons in the European Union Community and for which no satisfactory method of diagnosis, prevention, or treatment has been authorized (or the product would be a significant benefit to those affected).

Additionally, designation is granted for products intended for the diagnosis, prevention, or treatment of a life-threatening, seriously debilitating or serious and chronic condition and when, without incentives, it is unlikely that sales of the drug in the European Union would be sufficient to justify the necessary investment in developing the medicinal product.

In the European Union, orphan drug designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval.

This period may be reduced to six years if the orphan drug designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

Orphan drug designation must be requested before submitting an application for marketing approval.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

In the European Union, ODD entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval.

This period may be reduced to six years if the ODD criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

ODD must be requested before submitting an application for marketing approval.

ODD does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

European Union Pediatric Plan

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It is anticipated that the new Clinical Trials Regulation (EU) No 536/2014 may come into effect in late 2021with a three-year transition period for some types of clinical trials.

It will overhaul the current system of

approvals for clinical trials in the EU.

It will overhaul the current system of approvals for clinical trials in the EU.

Specifically, the new regulation, which will be directly applicable in all EU member states, aims at simplifying and streamlining the approval of clinical trials in the EU.

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Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases, or recommendations may be subject to scrutiny if they do not meet the requirements of a statutory or regulatory exception or safe harbor.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the U.S.

Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the

federal Anti-Kickback Statute.

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federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

The majority of states also have Anti-Kickback laws, which establish similar prohibitions and, in some cases, may apply to items or services reimbursed by any third-party payor, including commercial insurers.

The majority of states also have Anti-Kickback laws, which establish similar prohibitions and, in some cases, may apply to items or services reimbursed by any third-party payer, including commercial insurers.

The federal false claims and civil monetary penalties laws, including the civil False Claims Act, prohibit any person or entity from, among other things, knowingly presenting, or causing to be presented, a false, fictitious or fraudulent claim for payment to, or approval by, the federal government, knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or from knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S.

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Companies also have been prosecuted for allegedly violating the Anti-Kickback Statute and False Claims Act as a result of impermissible arrangements between companies and healthcare practitioners or as a result of the provision of remuneration by the companies to the healthcare practitioners.

In addition, the civil monetary penalties statute imposes penalties against any person who is determined to have presented or caused to be presented a claim to a federal health

program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

Many states also have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

In addition, the civil monetary penalties statute imposes penalties against any person who is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

Violations of fraud and abuse laws, including federal and state Anti-Kickback and false claims laws, may be punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid), disgorgement and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies.

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Given the significant size of actual and potential settlements, it is expected that the government authorities will continue to devote substantial resources to investigating healthcare providers’ and manufacturers’ compliance with applicable fraud and abuse laws.

The federal Health Insurance Portability and Accountability Act (“HIPAA”) of 1996 created additional federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

The federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) created additional federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third party payers, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the U.S.

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In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same requirements, thus complicating compliance efforts.

Animal Health Prescription Drugs

Under the FDCA, the term "drug"

means articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary;

articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals;

and articles other than food intended to affect the structure or any function of the body of man or other animals.

It also includes articles intended for use as a component of a drug.

Once a product is determined to be a drug for animal use, the next step is to determine whether or not it is a new animal drug.

The FDCA defines a new animal drug (in part) as any drug intended for use for animals other than man, the composition of which is not generally recognized, among experts qualified by scientific training and experience, as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling.

By virtue of Supreme Court interpretations of the necessary basis for general recognition, there are, for all practical purposes, no animal drugs which are not also new animal drugs.

Under the FDCA, a new animal drug may not be legally introduced into interstate commerce unless it is the subject of either:

● an approved NADA or abbreviated new animal drug application (ANADA) under section 512 of the Act;

● a conditional approval under section 571 of the FDCA;

● a listing on the Legally Marketed Unapproved New Animal Drug Index for Minor Species (the Index) under section 572 of the FDCA;

● an emergency use authorization (“EUA”) under section 564 of the FDCA (an EUA may only be issued under very limited circumstances, more information regarding EUAs is available at this webpage:

Emergency Use Authorization) ;

● an investigational exemption under section 512(j) of the FDCA.