Kamada Profile
Kamada Ltd. operates as a commercial stage global biopharmaceutical company. The company has a portfolio of marketed products indicated for rare and serious conditions.
The company is a leader in the specialty plasma-derived field focused on diseases of limited treatment alternatives. The company is also advancing an innovative development pipeline targeting areas of significant unmet medical need. The company’s strategy is focused on driving profitable growth from its significant commercial catalysts, as well as its manufacturing and development expertise in the plasma-derived and biopharmaceutical markets.
Segments
The company operates through two segments, Proprietary Products and Distribution.
The Proprietary Products segment, which includes its six FDA approved plasma-derived biopharmaceutical products - CYTOGAM, KEDRAB, WINRHO SDF, VARIZIG, HEPGAM B and GLASSIA, as well as KAMRAB, KAMRHO (D) and two types of equine-based anti-snake venom (ASV) products; all of which it markets internationally in more than 30 countries. The company manufactures its proprietary products at its cGMP compliant FDA-approved production facility located in Beit Kama, Israel, using its proprietary platform technology and know-how for the extraction and purification of proteins and IgGs from human plasma, as well as at third party contract manufacturing facilities.
The Distribution segment, in which it leverages its expertise and presence in the Israeli market by distributing, for use in Israel, more than 25 pharmaceutical products supplied by international manufacturers and has added eleven biosimilar products to its portfolio, which, subject to EMA and IMOH approvals, are expected to be launched in Israel through 2028.
As part of its Proprietary Products segment, the company sells CYTOGAM, a Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV), indicated for prophylaxis of CMV disease associated with solid organ transplantation in the United States and Canada.
The company markets KEDRAB, a human rabies immune globulin (HRIG), in the United States through a strategic distribution and supply agreement with Kedrion Biopharma (Kedrion).
The company sells WINRHO SDF, VARIZIG and HEPGAM B, in the United States, Canada and several other international markets, mainly in the Middle East and North Africa (MENA) regions.
The company markets GLASSIA in the United States through a strategic partnership with Takeda Pharmaceuticals Company Limited (Takeda). During 2021, Takeda completed the technology transfer of GLASSIA manufacturing to its facility in Belgium and received the required the U.S. Food and Drug Administration (FDA) approval and initiated its own production of GLASSIA for the U.S. market. In addition, during 2021, Takeda obtained a marketing authorization approval for GLASSIA from Health Canada.
The company also markets GLASSIA in other counties through local distributors. The company owns an FDA licensed plasma collection center that it acquired in March 2021 from the privately held B&PR based in Beaumont, Texas, which specializes in the collection of hyper-immune plasma used in the manufacture of KAMRHO (D). The company obtained FDA approval for the collection of hyper-immune plasma to be used in the manufacture of KEDRAB, which is plasma that contains high levels of antibodies from donors who have been previously vaccinated by an active rabies vaccine and plan to start collections of such plasma during 2023. The company also intends to leverage its FDA license to establish additional plasma collection centers in the United States, with the intention of collecting normal source plasma to be sold for manufacturing by third parties, as well as hyper-immune specialty plasma required for manufacturing of its proprietary products.
The company’s Distribution segment consist of sales in Israel of pharmaceutical products manufactured by third parties. The majority of the revenues generated in the company’s Distribution segment are from plasma-derived products manufactured by European companies, and its sales represented approximately 75% of its Distribution segment revenues for the years ended December 31, 2022.
In addition to its commercial operation, the company invests in research and development of new product candidates. The company’s leading investigational product is Inhaled AAT for AATD, for which it is continuing to progress the InnovAATe clinical trial, a randomized, double-blind, placebo-controlled, pivotal Phase 3 trial. The company has additional product candidates in early development stage.
The company continues to focus on driving profitable growth through expanding its growth catalysts which include: investment in the commercialization and life cycle management of its commercial Proprietary products, led by CYTOGAM and KEDRAB sales in the U.S. market; continued growth of its Proprietary hyper-immune portfolio’s revenues in existing and new geographic markets through registration and launch of the products in new territories; expanding sales of GLASSIA in ex-U.S. markets; generating royalties from GLASSIA sales by Takeda; expanding its plasma collection capabilities in support of its growing demand for hyper-immune plasma, as well as sales of normal source plasma to other plasma-derived manufacturers; continued increase of its Distribution segment revenues specifically through launching the eleven biosimilar products in Israel; and leveraging its FDA-approved IgG platform technology, manufacturing, research and development expertise to advance development and commercialization of additional product candidates, including its investigational Inhaled AAT product, and identify potential commercial partners for this product.
Commercial Product Portfolio
The company’s commercial products portfolio includes its proprietary plasma-derived biopharmaceutical products in its Proprietary Products segment, which are marked and sold directly or through strategic partners and local distributers in the U.S., Canada, and additional markets worldwide, as well as licensed products, some of which are plasma-derived, which are marketed and sold by it in its Distribution segment in Israel.
Proprietary Products segment
The company’s products in the Proprietary Products segment consist of plasma-derived protein and IgGs therapeutics derived from human plasma that are administered by injection or infusion. The company also manufactures anti-snake venom products from equine based serum.
Propriety Products
CYTOGAM
CYTOGAM (Cytomegalovirus Immune Globulin Intravenous (Human)) (CMV-IGIV) is indicated for CMV disease associated with the transplantation of the kidney, lung, liver, pancreas and heart. CYTOGAM is the sole FDA-approved immunoglobulin (IgG) product for this indication, and was acquired by the company from Saol Therapeutics Ltd. (Saol) in November 2021.
CYTOGAM is administered within 72 hours after transplantation and then at weeks 2, 4, 6, 8, 12 and 16 after transplantation. The precise dosage is adjusted according to patient’s weight. CMV seroprevalence in the U.S. is estimated at 50-80% among adults. CMV is typically passed through direct personal contact. A seropositive status indicates exposure to the virus and development of antibodies against CMV. After initial infection, CMV establishes lifelong latency in the host. Immunocompetent individuals possess few defenses, which protect mostly from infection and clinical symptoms (cell-mediated immunity). Immunocompromised patients, such as transplant patients, are vulnerable to both de novo and reactivation of CMV. In SOTs, seronegative recipients (R-) receiving seropositive organs (D+) have the highest risk of CMV infection and disease. The occurrence of disease caused by CMV in transplanted patients without prophylaxis in patients undergoing lung or heart-lung transplantation is 50%-75%, 9%-23% after heart transplantation, 22%-29% after liver transplantation, and 8%-32% after kidney transplantation. Investigational studies have shown that administration of CMV-IGIV is associated with neutralization of free CMV particles, which may lead to specific activation of the immune system, by raising relevant antibodies to levels capable of attenuating or reducing the incidence of serious CMV disease post-transplantation.
Based on the Organ Procurement and Transplantation Network (OPTN), in the U.S., there were more than 42,000 SOT procedures performed during 2022. The OPTN also suggests that the number of transplants each year continues to accelerate and in each of the past 11 years, new annual records have been set in the number of deceased donors nationwide. Transplantation has also increased as a result of greater and more successful usage of organs from less traditional donors, including older individuals and people who have died of cardiorespiratory failure. Several available antivirals (ganciclovir and valganciclovir) are being used and are considered standards of care for the prevention of CMV infection in high-risk patients. As CMV infection in immunocompromised solid organ transplant patients can be severe and life-threatening.
CYTOGAM is registered and sold in the United States and Canada. In addition, CYTOGAM is supplied on a named patient basis without registration in Qatar. The company plans to leverage its existing international distribution network to explore the opportunities to register and commercialize the product in other territories. In addition, the company is working with key opinion leaders (KOLs) in the U.S. to generate new clinical data in support of CYTOGAM and may explore future label expansion opportunities for the use of CYTOGAM in other indications.
The company obtained the approval from Health Canada for the transfer of the DIN in June 2022. The company received FDA acknowledgment for the transfer of the ownership of the U.S. BLA for CYTOGAM in September 2022. During December 2022, the company submitted an application to the FDA to manufacture CYTOGAM at the Beit Kama facility. The application was submitted as a PAS and FDA approval is expected by mid-2023. The anticipated FDA approval will mark the successful conclusion of the technology transfer process of CYTOGAM from the previous manufacturer, CSL Behring. The company’s available inventory of CYTOGAM is sufficient to meet market demand until the anticipated approval schedule.
KAMRAB/KEDRAB
KAMRAB is a hyper-immune plasma-derived therapeutic for prophylactic treatment against rabies infection that is administered to patients after exposure to an animal suspected of being infected with rabies. KAMRAB is administered by a one-time injection, and the precise dosage is a function of the patient’s weight (20 IU/kg).
KAMRAB has been sold by the company in various markets outside the United States through local distributors since 2003 and is sold in 15 countries, including Canada where it received marketing approval in November 2018, in various South American markets through the PAHO, the specialized international health agency for the Americas, and in Australia in which it received marketing approval in August 2021.
In July 2011, the company signed a strategic distribution and supply agreement with Kedrion for the clinical development and marketing in the United States of KAMRAB, pursuant to which Kedrion agreed to bear all the costs required for the Phase 2/3 clinical trials.
WINRHO SDF
WINRHO SDF is a Rho(D) Immune Globulin Intravenous (Human) product indicated for use in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage in the treatment of non-splenectomies, for Rho(D)-positive children with chronic or acute immune thrombocytopenia (ITP), adults with chronic ITP, and children and adults with ITP secondary to HIV infection. WINRHO SDF is also used for suppression of Rhesus (Rh) Isoimmunization during pregnancy and other obstetric conditions in non-sensitized, Rho(D)-negative women.
WINRHO SDF is registered and sold in 10 territories including the United States and Canada, as well as Egypt, Hong Kong, Kuwait, Saudi Arabia, South Korea, Turkey, the United Arab Emirates, and Uruguay. In ex-U.S. territories, the product is mainly used to treat HDN, and the company is continually evaluating with its existing international distribution network the registration and commercialization of the product in other territories.
The company obtained FDA acknowledgment for the transfer of the ownership of the BLA for WINRHO SDF in September 2022. The ownership transfer of the DIN was approved by Health Canada in June 2022, and the company is in the process of submitting requests to transfer the registration of the product in other international countries as applicable.
WINRHO SDF is manufactured by Emergent under a contract manufacturing agreement, which was assigned to the company by Saol following the consummation of the acquisition. The company’s KAMRHO (D) is a comparable product to WINRHO SDF and approved for HDN. The two products are registered and distributed in different markets.
HEPAGAM B
HEPAGAM B is a hepatitis B Immune Globulin (Human) (HBIg) product indicated to both prevent hepatitis B virus (HBV) recurrence following liver transplantation in hepatitis B surface antigen positive (HBsAg- positive) patients and to provide post-exposure prophylaxis treatment. HEPAGAM B, which was approved by the FDA in 2006 for post-exposure prophylaxis and in 2007 as a prevention therapy, was acquired by the company from Saol in November 2021.
HEPAGAM B is registered and sold in six territories including the United States, Canada, Turkey, Israel, the United Arab Emirates and Kuwait (in which territory sales have not yet initiated). In addition, HEPAGAM B is supplied on a named patient basis without registration in Moldova, Bahrain and Saudi Arabia (in which the registration process is on going).
FDA acknowledgment of ownership transfer of the BLA of HEPAGAM B was received in September 2022. Health Canada approval for the DIN transfer was obtained in October 2022. The company is in the process of submitting requests to transfer the registration of the product in other international countries as applicable.
HEPAGAM B is manufactured by Emergent under a contract manufacturing agreement which was assigned from Saol following the consummation of the acquisition.
VARIZIG
VARIZIG (Varicella Zoster Immune Globulin (Human)) is a product that contains antibodies specific for VZV, and it is indicated for post-exposure prophylaxis of varicella (chickenpox) in high-risk patient groups, including immunocompromised children, newborns, and pregnant women. VARIZIG is intended to reduce the severity of chickenpox infections in these patients. The CDC recommends VARIZIG for post-exposure prophylaxis of varicella for persons at high-risk for severe disease who lack evidence of immunity to varicella. VARIZIG, approved by the FDA in 2012, is the sole FDA-approved IgG product for this indication, and was acquired by the company from Saol in November 2021.
Varicella-zoster virus (VZV) causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness. Herpes zoster is caused by VZV reactivation. The incidence of herpes zoster increases with age or immunosuppression. Individuals at highest risk of developing severe or complicated varicella include immunocompromised people, preterm infants, and pregnant women. Varicella zoster immune globulin (human) (VARIZIG) is recommended by the CDC for post-exposure prophylaxis to prevent or attenuate varicella-zoster virus infection in high-risk individuals. VARIZIG may help these vulnerable patients to be defended against serious disease from varicella exposure. It has been demonstrated that post-exposure administration of VARIZIG was associated with low rates of varicella in high-risk patients.
VARIZIG is registered and sold in the United States and Canada. In addition, VARIZIG is supplied on a named patient basis or through a tender in Belgium, Kuwait, the Netherlands, Sweden, the United Arab Emirates, Norway, Denmark, and Estonia.
FDA acknowledgment of ownership transfer of the BLA of VARIZIG was received in September 2022. Health Canada approval for the DIN transfer was obtained in June 2022.
VARIZIG is manufactured by Emergent under a contract manufacturing agreement which was assigned from Saol following the consummation of the acquisition. In October 2022, the company was awarded an extension of an existing tender from the Canadian Blood Services (CBS) for the supply of the four IgG products, CYTOGAM, HEPAGAM, VARIZIG and WINRHO SDF, for an additional three years, commencing on April 1, 2023, securing the ongoing sales of those products in the Canadian market. CBS manages the Canadian supply of blood products for all Canadian provinces and territories, excluding Quebec. The company has an option to extend the agreement for up to two additional years. In addition, in Quebec, the company supplies CYTOGAM, HEPAGAM, VARIZIG and WINRHO SDF under the agreement with H’ema Quebec that was assigned to it from Saol.
GLASSIA
GLASSIA is an intravenous AAT product produced from fraction IV plasma that is indicated by the FDA for chronic augmentation and maintenance therapy in adults with emphysema due to congenital AATD. AAT is a naturally occurring protein found in a derivative of plasma known as fraction IV. AAT regulates the activity of certain white blood cells known as neutrophils and reduces cell inflammation. Patients with genetic AATD suffer from a chronic inflammatory state, lung tissue damage and a decrease in lung function.
GLASSIA is registered in 12 countries, of which it is being sold in the United States, Argentina, Israel and Russia. GLASSIA is also sold in South-Africa on a non-registered named-patient basis. During 2023-2024, the company expects to launch and sell GLASSIA in some of the additional countries where it is registered. The majority of sales of GLASSIA are in the United States, where it obtained FDA approval in July 2010 and sales commenced in September 2010. As part of the approval, the FDA requested that the company conducts post-approval Phase 4 clinical trials, as is common in the pharmaceutical industry, aimed at collecting additional safety and efficacy data for GLASSIA. The company markets GLASSIA in the United States through a strategic partnership with Takeda.
KAMRHO (D)
KAMRHO (D), similar to WINRHO SDF, is indicated for the prevention of HDN, which is a blood disease that occurs where the blood type of the mother is incompatible with the blood type of the fetus. KAMRHO (D) is produced from hyper-immune plasma and is administered through intra-muscular injection (KAMRHO (D) IM).
The company has completed the registration process for KAMRHO (D) in several countries and it sells it in seven countries, including Israel, as well as countries in Latin America, Asia, Africa and Eastern Europe.
SNAKE BITE ANTISERUM
The company’s snake bite antiserum products are used for the treatment of people who have been bitten by the most common Israeli viper (Vipera palaestinae) and by the Israeli Echis (Echis coloratus). The company’s snake bite antiserum products are produced from hyper-immune serum that has been derived from horses that were immunized against Israeli viper and Israeli Echis venom.
The company manufactures the snake bite antiserums pursuant to an agreement with the IMOH entered into in March 2009 and as extended and amended in November 2022. The agreement with the IMOH was initially entered into following a tender that the company wons, and the extension of the agreement was under an exemption from a tender. The agreement with the IMOH is currently in effect until September 2024.
Plasma Collection
As part of its strategy of evolving into a fully integrated specialty plasma company, the company established Kamada Plasma LLC, a newly formed wholly owned subsidiary, which operates its plasma collection activity in the United States. In March 2021, the comopany completed the acquisition of the FDA licensed plasma collection center and certain related assets from the privately held B&PR based in Beaumont, Texas, which specializes in the collection of hyper-immune plasma used in the manufacture of KAMRHO (D).
The company is in the process of significantly expanding its hyperimmune plasma collection capacity by investing in the acquired plasma collection center in Beaumont, Texas. The company obtained FDA approval for the collection of hyper-immune plasma to be used in the manufacture of KEDRAB, which is plasma that contains high levels of antibodies from donors who have been previously vaccinated by an active rabies vaccine and plan to start collections of such plasma during 2023. In addition, the company initiated a project to leverage its FDA plasma collection license to establish a network of new plasma collection centers in the United States, commencing in 2023, with the intention to collect normal source plasma for sale to other plasma-derived manufacturers, as well as hyperimmune specialty plasma required for manufacturing of its Proprietary products.
Distribution segment
Distribution segment consists of marketing and sales in Israel of pharmaceutical products manufactured by third parties. The company engages third party manufacturers, register their products with the IMOH, import the products to Israel, market, sell and distribute them to local HMOs, hospitals and pharmacists. The company’s primary products in the Distribution segment include pharmaceuticals for critical care delivered by injection, infusion or inhalation.
During 2021, the company added two additional products to the agreement, bringing the total number of products in the portfolio to eight. Alvotech’s pipeline includes biosimilar product candidates aimed at treating autoimmunity, oncology and inflammatory conditions. Subject to approval by the IMOH, the company expects to launch the first of these products, in Israel during 2023 and two others during 2024. Following receipt of the EMA marketing approval by Alvotech, and subject to subsequent approval by the IMOH, the remaining seven products included under the agreement with Alvotech are expected to be launched in Israel through 2028. In addition, in January 2021, the company announced its entering into agreements with two undisclosed international pharmaceutical companies to commercialize three additional biosimilar product candidates in Israel. Subject to approval by the EMA and subsequently by the IMOH, the three products are expected to be launched in Israel through 2026. The two pharmaceutical companies will maintain development, manufacturing and supply responsibilities for these three products.
The following table sets forth the company’s primary products in the Distribution segment.
Respiratory
BRAMITOB: Management of chronic pulmonary infection due to pseudomonas aeruginosa in patients six years and older with cystic fibrosis.
FOSTER: Regular treatment of asthma where use of a combination product (inhaled corticosteroid and long-acting beta2-agonist) is appropriate.
TRIMBOW: Maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD)with Asthma Maintenance treatment of asthma.
PROVOCHOLINE: Diagnosis of bronchial airway hyperactivity in subjects who do not have clinically apparent asthma.
AEROBIKA: OPEP device.
RUPAFIN: Symptomatic treatment of Allergic rhinitis and Urticaria.
RUPAFIN ORAL SOLUTION: Symptomatic treatment of allergic rhinitis in children aged 2 to 11 years and urticaria in children aged 2 to 11 years.
Immunoglobulins
IVIG: Treatment of various immunodeficiency-related conditions.
VARITECT: Preventive treatment after exposure to the virus that causes chicken pox and zoster herpes.
ZUTECTRA: Prevention of hepatitis B virus (HBV) re-infection in HBV-DNA negative patients 6 months after liver transplantation for hepatitis B induced liver failure.
HEPATECT CP: Prevent contraction of Hepatitis B by adults and children older than two years.
MEGALOTECT CP: Contains antibodies that neutralize CMV viruses and prevent their spread in immunologically impaired patients.
RUCONEST: Treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency.
Critical Care
HEPARIN SODIUM INJECTION: Treatment of thrombo-embolic disorders such as deep vein thrombosis, acute arterial embolism or thrombosis, thrombophlebitis, pulmonary embolism, fat embolism. Prophylaxis of deep vein thrombosis and thromboembolic events.
ALBUMIN and ALBUMIN: Maintains a proper level in the patient’s blood plasma.
Coagulation Factors
Factor VIII: Treatment of Hemophilia Type A diseases.
Factor IX: Treatment of Hemophilia Type B disease.
COAGADEX: Treatment specifically for hereditary factor X deficiency.
Vaccinations
IXIARO: Active immunization against Japanese encephalitis in adults, adolescents, children and infants aged 2 months and older.
VIVOTIF: Immunization against disease caused by Salmonella Typhi.
Metabolic Disease
PROCYSBI: Nephropathic cystinosis in adults and children 1 year of age and older.
LAMZEDE: Treatment of alpha-mannosidosis
Oncology
ELIGARD: Management of advanced prostate cancer.
Development Product Pipeline
The company’s research and development activities include conducting pre-clinical and clinical trials and other development activities for its Propriety pipeline products, improving existing products and processes, conducting development work at the request of regulatory authorities and strategic partners, as well as communicating with regulatory authorities regarding its commercial products and clinical and development programs. The company incurred approximately $13.2 million in research and development expenses in the years ended December 31, 2022.
The company is in various stages of pre-clinical and clinical development of new product candidates for its Proprietary Products segment.
Inhaled Formulations of AAT for AATD
The company is in the process of clinical development of an inhaled formulation of AAT administered through the use of a nebulizer. The nebulizer was developed by PARI. Inhaled AAT for AATD has been designated as an orphan drug for the treatment of AATD in the United States and Europe.
The company has been able to leverage its expertise gained from the production of GLASSIA to develop a stable, high-purity Inhaled AAT product candidate for the treatment of AATD. Existing treatment for AATD require weekly intravenous infusions of AAT therapeutics.
The company conducted a double-blind randomized placebo-controlled Phase 2/3 pivotal trial, under EMA guidance, which was completed at the end of 2013. A total of 168 patients participated in the trial in seven countries in Europe and Canada. Subjects in this trial were administered with a twice daily treatment of Inhaled AAT or equivalent dose of placebo for 50 consecutive weeks.
During March 2014, the company initiated a Phase 2 trial in the United States. The trial was completed in May 2016. This trial was intended to serve as a supplementary trial to the European Phase 2/3 trial and was designed to incorporate parameters required by the FDA. This Phase 2, double-blind, placebo-controlled study explored the Endothelial Lining Fluid (ELF) and plasma concentration as well as safety of Inhaled AAT in AATD subjects. The subjects received one of two doses of Inhaled AAT or placebo. The study involved the daily inhalation of 80 mg or 160 mg of human AAT or placebo via the eFlow device for 12 weeks. Following the 12-week double blind period, the subjects were offered to participate in an additional 12 weeks open label period during which they receive only Inhaled AAT therapy. In December 2015, the company completed the enrollment of patients in the study and in August 2016 the company reported positive top-line results, according to which the company met the primary endpoint. Finally, aerosolized M-specific AAT was detected in the plasma of all subjects receiving Inhaled AAT, consistent with what was seen in the Phase 2/3 clinical trial of the company’s Inhaled AAT conducted in the EU.
The company filed the MAA for its Inhaled AAT for AATD during the first quarter of 2016 and in June 2017 the company withdrews the MAA, as following extensive discussions with the EMA the company concluded that the EMA did not view the data submitted as sufficient, in terms of safety and efficacy, for approval of the MAA, and that the supplementary data needed for approval required an additional clinical trial.
In addition to the pivotal study and based on feedback received from the FDA regarding ADAs to Inhaled AAT, the company intends to concurrently conduct a sub-study in North America in which approximately 30 patients will be evaluated for the effect of ADA on AAT levels in plasma with Inhaled AAT and IV AAT treatments. The company already obtained FDA acceptance of the protocol design for the study; and its initiation is planned for 2024.
The company continues to evaluate partnering opportunities for the development and commercialization of this pipeline product.
Anti-SARS-CoV-2 IgG Product as a Potential Treatment for COVID-19
In response to the COVID-19 outbreak, in early 2020 the company initiated the development of a human plasma-derived Anti-SARS-CoV-2 polyclonal immunoglobulin (IgG) product using its proprietary plasma derived IgG platform technology as a potential treatment for COVID-19. The development of the company’s investigational Anti-SARS-CoV-2 IgG product was done with full cooperation with IMOH. The product was developed in line with the requirement of Ph Eur for IVIG product and based on the company’s established technology platform for IgG, as approved in the United States, Israel and other international markets.
In June 2020, the company’s Anti-SARS-CoV-2 IgG product became available for compassionate use treatment in Israel, and in August 2020, the company initiated a Phase 1/2 open-label, single-arm, multi-center clinical trial in Israel of the product. A total of 12 eligible patients (age 34-69) were enrolled in the trial and received the company’s product at a single dose of 4 grams IgG within five to 10 days of initial symptoms. Patient follow-up occurred for 84 days. In March 2021, the company announced top-line results for the Phase 1/2 clinical trial, according to which symptoms improvement was observed in 11 of the 12 patients within 24 to 48 hours from treatment.
In October 2020, the company signed an agreement with the IMOH to supply its investigational Anti-SARS-CoV-2 IgG product for the treatment of COVID-19 patients in Israel. The company manufactured the product, which was supplied to the IMOH, from convalescent plasma collected and supplied by the Israeli National Blood Services, a division of Magen David Adom (MADA), as well as plasma collected by Kedrion in the U.S.
Recombinant AAT
During 2020, the company initiated the development of recombinant human Alpha 1 Antitrypsin (rhAAT) product. The company engaged Cellca a CDMO located in Germany, part of Sartorius Stedim BioTech Group, to pursue the cell line development of the rhAAT in Chinese Hamsters Ovaries. During 2022, the company studied the clones previously selected using in vitro and in vivo models, elucidating the immuno-modulatory properties of the protein.
Other Early-Stage Development Programs
During 2022, the company initiated three new early-stage development programs of plasma derived product candidates. These programs include a human plasma-based eye drop for potential treatment of several conditions; (ii) an automated portable small scale system for extraction and purification of hyperimmune IgG from convalescent plasma, at the hospital/blood bank setting, for immediate response to a variety of unmet medical needs, including pandemic outbreaks, as well as possible treatment of currently neglected or untreated viral diseases; and (iii) a hyperimmune anti-tuberculosis IgG as a potential complementary treatment to existing standard of care, the program is developed in collaboration with the Clinical Microbiology and Immunology department of the Medicine-Sackler Faculty of Tel Aviv University and is partially funded by the Israel Innovation Authority.
The company plans to advance these programs until completion of proof-of-concept, at which point it plans to evaluate continued internal development, partnering or out-licensing.
Strategic Partnerships
Kedrion (KAMRAB/KEDRAB)
On July 18, 2011, the company signed an agreement with Kedrion, an international company that collects and fractionates blood plasma to produce and distribute plasma-derived therapeutic products for use in treating serious diseases, disorders and conditions such as hemophilia and immune system deficiencies, with market presence in about 100 countries. The agreement provided for exclusive cooperation on completing the clinical development, and marketing and distribution of its anti-rabies immunoglobulin, KAMRAB, in the United States under the brand name KEDRAB, if the product is approved. The agreement provides exclusive rights to Kedrion to market and sell KEDRAB in the United States. The company retains intellectual property rights to KEDRAB. Kedrion is obligated to purchase a minimum amount of KEDRAB per year during the term of the agreement.
Takeda (GLASSIA)
The company has a partnership arrangement with Takeda that includes three main agreements: an exclusive manufacturing, supply and distribution agreement, pursuant to which until November 2021 it manufactured GLASSIA for sale to Takeda for further distribution in the United States, Canada, Australia and New Zealand; a technology license agreement, which grants Takeda licenses to use its knowledge and patents to produce, develop and sell GLASSIA; and a fraction IV-I paste supply agreement, pursuant to which Takeda supplies it with fraction IV plasma, a plasma derivative, produced by Takeda.
The agreements were originally executed with Baxter in August 2010. During 2015, Baxter assigned all its rights under the agreements to Baxalta, an independent public company which spun-off from Baxter. In 2016, Shire completed the acquisition of Baxalta, and as a result, all of Baxalta’s rights under the agreements were assigned to Shire. In January 2019, Takeda completed its acquisition of Shire, and all rights under the agreement transferred to Takeda.
Exclusive Manufacturing, Supply and Distribution Agreement
Pursuant to the exclusive manufacturing, supply and distribution agreement, as amended from time to time, Takeda was obligated to purchase a minimum amount of GLASSIA per year until the end of 2021. In November 2021, pursuant to the technology license agreement, Takeda completed the technology transfer of GLASSIA manufacturing, and initiated its own production of GLASSIA for the U.S. market. Accordingly, the company completed the supply of GLASSIA to Takeda and, while for a certain period of time the company is still an approved supplier of the product.
Technology License Agreement
The technology license agreement provides an exclusive license to Takeda, with the right to sub-license to certain manufacturing parties, of the company’s intellectual property and know-how regarding the manufacture and additional development of GLASSIA for use in Takeda’s production and sale of GLASSIA in the United States, Canada, Australia and New Zealand. Pursuant to the technology license agreement, the company was entitled to receive payments for the achievement of certain development-based milestones related to the transfer of technology to Takeda and sales-based milestones.
During the fourth quarter of 2021 Takeda received an approval from Health Canada for the marketing and distribution of GLASSIA in Canada. The technology license agreement expires in 2040.
PARI
On November 16, 2006, the company entered into a license agreement with PARI (the Original PARI Agreement) regarding the clinical development of an inhaled formulation of AAT, including Inhaled AAT for AATD, using PARI’s eFlow nebulizer. Under the Original PARI Agreement, the company received an exclusive worldwide license, subject to certain preexisting rights, including the right to grant sub-licenses, to use the eFlow nebulizer, including the associated technology and intellectual property, for the clinical development, registration, and commercialization of inhaled formulations of AAT to treat AATD and respiratory deterioration, and to commercialize the device for use with such inhaled formulations.
On February 21, 2008, the company entered into an addendum to the Original PARI Agreement (together with the Original PARI Agreement, the PARI Agreement), which extended the exclusive global license granted to it to use the eFlow nebulizer, including the associated technology and intellectual property, for the clinical development, registration and commercialization of Inhaled AAT for two additional indications of lung disease, namely cystic fibrosis and bronchiectasis.
In May 2019, the company signed a Clinical Study Supply Agreement (CSSA) with PARI for the supply of the required quantities of PARI’s eTrack controller kits and the PARItrack web portal associated with PARI’s eFlow nebulizer required for its pivotal Phase 3 InnovAATe clinical trial and for the FDA required HFS. The CSSA is a supplement agreement to the PARI Agreement and will expire upon the expiration or termination of the PARI Agreement.
On February 21, 2008, the company also signed a commercialization and supply agreement with PARI that provides for the commercial supply of the eFlow nebulizer and its spare parts to patients who may be treated with the inhaled formulation of AAT, if approved, either through its own distributors, its distributors or independent distributors in countries where PARI does not have a distributor.
Manufacturing and Supply
HEPAGAM B, VARIZIG and WINRHO SDF, which the company acquired in November 2021, are manufactured by Emergent under a manufacturing services agreement the company assumed as part of the acquisition of the portfolio from Saol. Under the agreement, Emergent serves as the exclusive manufacturer of the products for distribution in certain jurisdictions.
Raw Materials
Hyper-immune Plasma
In January 2012, the company entered into a plasma purchase agreement with Kedplasma, a subsidiary of Kedrion, for the supply of anti-rabies hyper-immune plasma required for the manufacturing of KAMRAB (including for manufacturing of KEDRAB for sale to Kedrion for further distribution in the U.S. market).
CMV hyper-immune plasma for the manufacturing of CYTOGAM is supplied by CSL Behring under an agreement that was assigned to the company from Saol in connection with the acquisition.
Plasma derived Fraction IV paste for GLASSIA manufacturing
On August 23, 2010, in conjunction with the partnership arrangement with Takeda, the company signed a fraction IV paste supply agreement with Takeda for the supply of fraction IV for use in the production of GLASSIA to be sold in the United States. Under this agreement, Takeda also supplies the company with fraction IV to continue the development, pre-clinical and clinical studies of GLASSIA and other AAT derived products and for the production, sale and distribution of GLASSIA in jurisdictions other than those which are covered under the exclusive manufacturing, supply and distribution agreement with Takeda, as well as for other AAT derived products.
The supply agreement terminates on August 23, 2040, subject to an option for earlier termination in the event of a material breach.
Marketing and Distribution
The company distributes its Proprietary products in more than 30 countries world-wide, including the U.S., Canada, Russia, Argentina, Israel, India, Turkey, Australia and several other countries in Europe, Latin America, Asia, and the MENA region. The company is also a supplier to the PAHO, the specialized international health agency for the Americas. The company distributes its products in these markets directly, through strategic partners (e.g., Kedrion in the U.S. market) and local distributers. The company typically receives orders for its products and receive requests for participation in tenders for the supply of its products from its existing distributors, as well as from new potential distributors.
The company sells KEDRAB to Kedrion for distribution in the U.S. market and sells KAMRAB and KAMRHO (D) to other distributers in non-U.S. countries. Through 2021, the company sold GLASSIA to Takeda for further distribution in the U.S. market and it sells the product to other distributors in non-U.S. countries. In the Israeli market, the company sells and distributes GLASSIA, KAMRAB and KAMRHO (D) independently to local HMOs and medical centers, or through a third party logistic partner that specializes in the supply of equipment and pharmaceuticals to healthcare providers, and in addition the company sells its anti-snake venom to the IMOH.
The company distributes CYTOGAM, HEPAGAM B, VARIZIG and WINRHO SDF in the U.S. market directly to wholesalers and local distributors, through its wholly owned U.S. subsidiary, Kamada Inc. Through August 2022, and pursuant to the terms of the transition services agreement, the company relied on Saol to manage and oversee the U.S. distribution of these products. Commencing September 2022, the company assumed all distribution responsibilities for these products in the U.S. market and are utilizing a U.S. 3PL provider for the distribution, which provides complete order to cash services. The company is also responsible for marketing activities, price determination, provision of rebates and credits, as well as mandatory pricing reporting requirements for these products in the U.S. market. The company distributes these products in non-U.S. countries, primarily Canada and the MENA region, through engagement of local distributors.
The company intends to leverage its existing strong international distribution network to expand the sales of CYTOGAM, HEPAGAM B, VARIZIG and WINRHO SDF to existing markets it operates in and furthermore, it intends to explore the expansion of sales of its products, primarily GLASSIA and KAMRAB to the new international markets the company assumed following the acquisition of the new product portfolio, primarily in the MENA region.
As part of the establishment of its direct presence in the U.S. market, during 2022 the company deployed a team of U.S. based experienced sales and medical affairs professionals who have rapidly established its operations in this key market. The U.S. sales team is promoting its portfolio of specialty plasma-derived IgG products to physicians and other healthcare practitioners through direct engagement and opportunities at medical conventions. The Medical Affairs team is working to educate physicians, while addressing their scientific and clinical inquiries, including participating in major medical conferences in the U.S. These activities represent the first time in over a decade that these hyper-immune specialty products have been supported by field-based activity in the United States. The company encouraged by positive feedback received from key U.S. physicians who are seeking to publish new clinical data related to its portfolio, and are conducting educational symposiums that will have a positive impact on the understanding of these products, thereby contributing to continued growth in demand.
Outside the U.S. market, the company’s distributors sell its products through a tender process and/or the private market. The tender process is conducted on a regular basis by the distributors, sometimes on an annual basis. The company is establishing its footprint in the MENA region as a leader in the specialty plasma-derived field by exploring geographical expansion opportunities and strengthening its relationships with KOLs across the region.
Most of the company’s sales outside of Israel are made against open credit and some in documentary credit or advance payment. Most of the company’s sales inside Israel are made against open credit or cash. The credit given to some of its customers abroad (except for sales in documentary credit or advanced payment) is mostly secured by means of a credit insurance policy and in certain cases with bank guarantees.
In the Distribution segment, the company markets its products in Israel to HMOs and hospitals on its own or through third party logistic associates. The company sells certain of its Distribution products through offers to participate in public tenders that occur on an annual basis or through direct orders. The public tender process involves HMOs and hospitals soliciting bids from several potential suppliers, including the company, and selecting the winning bid based on several attributes, the primary attributes are generally price and availability. The annual public tender process is also used by the company’s existing customers to determine their suppliers.
To secure supply of its products in the Distribution segment, the company enters into supply and distribution agreements with the product manufacturers, pursuant to which it undertakes to register the products with the IMOH, acquire certain quantity of products and act as the product distributor in the Israeli market.
Research and Development Expenses
For the year ended December 31, 2022, the company incurred $13.2 million of research and development expenses.
Customers
For the year ended December 31, 2022, sales to the company’s three largest customers, Kedrion, Takeda and Clalit Health Services, an Israeli HMO, accounted for 13%, 11% and 9%, respectively, of its total revenues.
While Kedrion, Takeda and Clalit Health Services continue to be the company’s major customers in the Proprietary Products segment, other key customers in the segment include McKesson and Cardinal Health, two of the largest U.S. based wholesalers, PAHO, two Canadian customers and the company’s distributors in Argentina, Russia, Thailand, India, Brazil, the MENA region and other territories.
The company’s primary customers in the Distribution segment in Israel are HMOs, including Clalit Health Services and Maccabi Healthcare Services, as well as local hospitals.
Intellectual Property
Patents
As of December 31, 2022, the company owned for use within its field of business eleven families of patents and patent applications, all of which are granted or pending, respectively, in the United States, most were also filed in Europe, Canada and Israel and some were additionally filed in Russia, Turkey, certain Latin American countries, Australia and other countries, including one PCT provisional applications. At present, one patent family protecting the company’s manufacturing process of GLASSIA is considered to be material to the operation of its business as a whole. Such patent has been issued in a variety of jurisdictions, including Australia, Austria, Belgium, Canada, Denmark, Estonia, Israel, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Slovenia, Poland, Spain, Portugal, Sweden, Switzerland, Turkey, the United Kingdom and the United States, and is due to expire in 2024. In addition, the company owns a patent family protecting pulmonary delivery of Alpha 1 antitrypsin, filed in 2007, in a variety of jurisdictions, including Canada, Germany, France, Italy, the Netherlands, Ireland, Belgium, Great Britain, Israel, Russia and Mexico. Furthermore, the comopany owns a patent family filed in 2018, protecting its manufacturing process of immunoglobulins. This patent family includes pending applications in the U.S., Canada, Europe and Israel.
The company’s patents generally relate to the separation and purification of proteins and their respective pharmaceutical compositions. The company’s patents and patent applications further relate to the use of its products for a variety of clinical indications, and their delivery methods. The company’s patent applications further relate to the production of recombinant AAT-1 and uses thereof for clinical indications. The company’s patents and patent applications are expected to expire at various dates between 2024 and 2040. The company also relies on trade secrets to protect certain aspects of its separation and purification technology.
Trademarks
The company relies on trade names, trademarks and service marks to protect its name brands. The company’s registered trademarks in several countries, such as United States and the European Union, Israel, and certain Latin American countries, include the trademarks CYTOGAM, GLASSIA, HEPAGAM, HEPAGAM B, KAMRAB, KEDRAB, KAMADA, KAMRHO, KAMRHO-D, KAMRHO-D IM, KR (design mark), REBINOLIN, ????????? (Rebinolin in Cyrillic), RESPIKAM, KAMADA RESPIRA, VARIZIG, VENTIA, WINRHO and WINRHO SDF. Regarding the trademarks CYTOGAM, WINRHO, HEPAGAM and VARIZIG the company is in a process of transferring these registrations in its name in several territories.
Competition
The company’s Proprietary Products compete with products distributed by well-established biopharmaceutical companies, including several large competitors in the plasma industry. These large competitors include CSL Behring Ltd. (CSL), Takeda, and Grifols S.A. (Grifols), which acquired a previous competitor, Talecris Biotherapeutics, Inc. (Talecris) in 2011, Octapharma, Kedrion (other than for KEDRAB), Biotest AG and ADMA Biologics Inc. (ADMA).
In the United States, WINRHO SDF competes with corticosteroids (oral prednisone or high-dose dexamethasone) or IVIG (Grifols, CSL and Takeda are the main IVIG manufacturers and suppliers in the U.S.) as first line treatment of acute ITP, with IVIG or WINRHO SDF recommended for pediatric patients in whom corticosteroids are contraindicated. IVIG has similar efficacy to WINRHO SDF, and ITP is its labeled indication for IVIG. Rhophylac (CSL Behring) is also approved for ITP treatment. There are several competing products to Glassia. Grifols, CSL and Takeda have competing plasma derived AAT products approved for AATD and are marketed in the U.S. as well in some countries in the EU.
Government Regulations
All of the company’s products for human use and product candidates in the United States, are regulated by the FDA as biologics. The manufacturing of the company’s product candidates is required to comply with applicable FDA manufacturing requirements contained in the FDA’s cGMP regulations.
In the United States, the company’s activities are potentially subject to regulation and enforcement by various federal, state and local authorities in addition to the FDA, including the Centers for Medicare and Medicaid Services other divisions of the HHS OIG, the U.S. Federal Trade Commission, the U.S. Department of Justice and individual United States Attorney’s offices within the Department of Justice, state attorneys general and state and local governments. To the extent applicable, the company must comply with the fraud and abuse provisions of the Social Security Act, the federal Anti-Kickback Statute, the FCA, the privacy and security provisions of HIPAA, and similar state laws, each as amended. Pricing and rebate programs must comply with the Medicaid rebate requirements of the Omnibus Budget Reconciliation Act of 1990 and the VHCA, each as amended.
History
Kamada Ltd. was founded in 1990. The company was incorporated under the laws of the state of Israel in 1990.
