Candidate: Bamlanivimab (LY-CoV555)
Type: Anti-SAR-CoV-2 antibody based on AbCellera’s rapid pandemic response platform
2021 Status: 220,000 DOSES FOR EU—AbCellera, Eli Lilly’s partner in developing Bamlanivimab, said September 21 that Lilly and the European Commission had agreed to supply up to 220,000 doses of bamlanivimab together with etesevimab to treat confirmed COVID-19 in patients aged 12 years and older that do not require supplemental oxygen for COVID-19 and who are at increased risk of progressing to severe COVID-19.
No value was disclosed for the Joint Procurement Agreement, which is designed to enable participating countries in the European Union (EU) and European Economic Area (EEA) to purchase the products directly from Lilly following national approval for emergency use or marketing authorization at the EU level.
As of September 21, Lilly said, bamlanivimab alone and together with etesevimab had been used to treat more than 535,000 patients in the U.S., potentially keeping more than 25,000 patients out of the hospital and saving more than 10,000 lives.
FDA EXPANDS EUA FOR COMBO—The FDA on September 16 expanded the Emergency Use Authorization (EUA) granted to Eli Lilly for the combination of bamlanivimab and etesevimab by allowing its use for post-exposure prophylaxis (PEP) in high-risk individuals 12 years of age and older who have not been fully vaccinated against COVID-19 or are not expected to mount an adequate immune response to complete vaccination, and have been exposed to someone infected with SARS-CoV-2 or who are at high risk of exposure in an institutional setting, including a nursing home or prison.
Lilly said the expanded authorization was based on data from the Phase III BLAZE-2 trial (NCT04497987), which showed that bamlanivimab 4200 mg reduced the risk of contracting symptomatic COVID-19 by up to 80% in nursing home residents, and up to 57% among residents and staff of long-term care facilities. BLAZE-2 was conducted by Lilly with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the COVID-19 Prevention Network (CoVPN).
According to the company, over 535,000 treatment courses of bamlanivimab or bamlanivimab and etesevimab together have been administered to patients as of September 16.
$330M U.S. Gov’t Purchase—The U.S. government will purchase an additional 388,000 doses of etesevimab to complement doses of bamlanivimab previously purchased by the government, Lilly said September 15, in a deal expected to generate $330 million in the second half of 2021. Approximately 200,000 doses are expected to ship during Q3 and the rest in Q4.
Antibody Combination Distribution Resumed— On September 2, the FDA and the U.S. Assistant Secretary for Preparedness and Response (ASPR) announced the authorization of the use of bamlanivimab and etesevimab, administered together, in all U.S. states, territories, and U.S. jurisdictions where recent data has shown the combined frequency of variants resistant to the combination was less than or equal to 5%.
Upon that basis, such authorization had been granted August 27 for use of the combination in 22 U.S. states: Colorado, Connecticut, Illinois, Indiana, Iowa, Kansas, Maine, Massachusetts, New Hampshire, Michigan, Minnesota, Missouri, Montana, Nebraska, North Dakota, Ohio, Rhode Island, South Dakota, Utah, Vermont, Wisconsin, and Wyoming.
Shelf Life Extension—On August 20, the FDA and ASPR extended from 12 months to 18 months the shelf life of bamlanivimab under its Emergency Use Authorization for the combination with etesevimab.
Antibody Combination Distribution Halted—The FDA and the U.S. Assistant Secretary for Preparedness and Response (ASPR) said June 25 they immediately paused all nationwide distribution of Eli Lilly’s antibody combination of bamlanivimab and etesevimab.
ASPR said the combination showed itself “not active” against two COVID-19 variants. P.1/Gamma (first identified in Brazil) and B.1.351/Beta (first identified in South Africa) have shown significantly reduced susceptibility against bamlanivimab-etesevimab, the FDA acknowledged in its “Fact Sheet” for healthcare providers of detailed instructions for administering the antibody combination.
The FDA recommended that healthcare providers nationwide use two other monoclonal antibody therapies that have been granted EUAs—Regeneron Pharmaceuticals’ two-antibody “cocktail” or combination REGEN-COV™; and Sotrovimab (formerly VIR-7831), which is being developed by GlaxoSmithKline (GSK) and Vir Biotechnology.
Eli Lilly said its antibody combination of bamlanivimab (LY-CoV555) 700 mg and etesevimab (LY-CoV016) 1400 mg—already FDA-authorized for emergency use—generated additional positive Phase III results, slashing by 87% the risk of COVID-19 related hospitalizations and deaths in high-risk patients recently diagnosed with the virus.
Four hospitalizations and deaths, or “events,” occurred in patients 29 days after treatment with the bamlanivimab-etesevimab combination, compared with 15 reported in patients given placebo in the randomized, double-blind, placebo-controlled BLAZE-1 Phase III trial (NCT04427501), Lilly said.
The data came from a newly reported cohort of 769 high-risk patients aged 12 and older with mild to moderate COVID-19. Of those patients, 511 were randomized to therapy, and the other 258 to placebo. The study’s key endpoint was the percentage of participants who experience COVID-related hospitalizations or death from any cause by day 29.
Lilly added that bamlanivimab and etesevimab together also showed statistically significant improvements on key secondary endpoints—defined as change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV-2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit, or death from any cause from baseline by day 29. Additional endpoints in BLAZE-1 included change from baseline in viral load at other time points, symptom improvement, symptom resolution, as well as safety.
Positive CHMP opinion—The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on March 5 issued a positive opinion on bamlanivimab alone as well as bamlanivimab administered together with etesevimab. Both options can be used for the treatment of confirmed COVID-19 in patients aged 12 years and older that do not require supplemental oxygen for COVID-19 and who are at high risk of progressing to severe COVID-19, the CHMP advised.
The CHMP based its opinion on results from the Phase II and Phase III portions of the BLAZE-1 trial (NCT04427501), which showed in part that bamlanivimab alone reduced viral load and symptoms and also reduced COVID-19 hospitalizations by approximately 70%.
100,000 Doses of Combo for $210M—Lilly said February 26 that the U.S. government agreed to purchase a minimum of 100,000 doses of the combination therapy of bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) for $210 million, with doses set to be delivered through March 31, 2021. The U.S. government will have the option to purchase up to an additional 1.1 million doses of the combination through November 25, 2021, under the same terms as the base agreement and subject to agreement from Lilly, product availability and the medical need in the U.S.
The government has already committed to purchase a total of 1.45 million doses of bamlanivimab alone, which includes more than 1 million doses that have been delivered, and an agreement to deliver 450,000 additional doses by March 31. The government has promised to provide neutralizing antibodies at no out-of-pocket cost to patients, while acknowledging that healthcare facilities may charge a fee for the product’s administration.
Emergency Use with Etesevimab Authorized—The FDA on February 9 granted Emergency Use Authorization (EUA) for bamlanivimab (LY-CoV555) 700 mg in combination with etesevimab (LY-CoV016) 1400 mg for the treatment of mild to moderate COVID-19 in patients aged 12 and older who are at high risk for progressing to severe COVID-19 and/or hospitalization.
The FDA also authorized infusion times of 16 minutes for bamlanivimab and 21 minutes for the bamlanivimab-etesevimab combination—compared with the previously authorized time of 60 minutes. Lilly said it reduced the infusion times in response to feedback received from nurses and doctors administering the infusions.
The EUA is based on Phase III data from the Phase III BLAZE-1 trial (NCT04427501), which demonstrated bamlanivimab and etesevimab together reduced the risk of COVID-19 hospitalizations and death by 70%. These data replicate earlier results published in JAMA in a much larger group of patients. Lilly said the outcomes seen with bamlanivimab and etesevimab together were consistent with the reduction in risk of hospitalization or ER visits seen with bamlanivimab alone. The most common adverse event more often reported for patients receiving bamlanivimab and etesevimab together vs. placebo was nausea on the day of infusion.
The U.S. Department of Defense (DoD) disclosed January 27 that the Army increased to $625 million its contract with Eli Lilly (W911QY-21-C-0016) for of bamlanivimab to be made at a Lilly production site in Indianapolis, raising the quyantity to be produced to 500 million doses. The contract, awarded by U.S. Army Contracting Command, originally covered an unspecified quantity of bamlanivimab valued at $312.5 million. Funds for the Lilly contract will come from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, enacted March 27.
Lilly said its authorized bamlanivimab (LY-CoV555), in combination with another of its antibody candidates, etesevimab (LY-CoV016), met the primary endpoint of the Phase III BLAZE-1 trial (NCT04427501) by significantly reducing COVID-19-related hospitalizations and deaths in high-risk patients recently diagnosed with COVID-19.
Of the 10 patients who died during the study, all were randomized to placebo, Lilly added.
Lilly reported 11 events (2.1%) in patients receiving its antibody combination, compared with 36 events (7%) in placebo patients—a 70% risk reduction among the study’s 1,035 patients. That decrease was consistent with the reduction in risk of hospitalization or ER visits seen with bamlanivimab alone in the Phase II portion of BLAZE-1, the company said.
The bamlanivimab-etesevimab combo also showed statistically significant improvements on all four key secondary endpoints—the change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit or death from any cause from baseline by day 29.
The results marked the second time in less than a week that Lilly announced a positive clinical outcome for bamlanivimab.
On January 21, the company trumpeted findings from its BLAZE-2 trial (NCT04497987), saying that bamlanivimab significantly reduced the risk of contracting symptomatic COVID-19 among residents and staff of long-term care facilities compared with placebo after eight weeks. Lilly said that 299 SARS-CoV-2 negative residents randomized to bamlanivimab had up to an 80% lower risk of contracting COVID-19 versus residents in the same facility randomized to placebo.
BLAZE-2 enrolled 965 participants who tested negative for SARS-CoV-2 at baseline (299 residents and 666 staff), and 132 participants (41 residents and 91 staff) who tested positive. Lilly is conducting BLAZE-2 with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the COVID-19 Prevention Network (CoVPN).
2020 Status: Eli Lilly and UnitedHealth Group said December 4 they would partner on a “pragmatic” study of bamlanivimab in high-risk, COVID-19 infected individuals. The study will draw upon both UnitedHealth Group’s UnitedHealthcare health benefits business and its Optum health services business to detect and treat high-risk symptomatic patients who test positive for COVID-19 with bamlanivimab. Patients will receive daily symptom tracking, in-home SARS-CoV-2 testing and in-home infusion services allowing them to stay quarantined and at home, minimizing the potential spread of COVID-19.
A day earlier, Lilly said that the U.S. government exercised its option to purchase another 650,000 vials of bamlanivimab from the company for $812.5 million through January 31, 2021, under the contract through which the government bought an initial 300,000 vials over two months for $375 million—$1,250 a vial—to be provided by the Biomedical Advanced Research and Development Authority (BARDA) partnered with the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and Army Contracting Command.
The contract is part of Operation Warp Speed, the Trump administration’s program designed to accelerate the development, manufacturing, and distribution of COVID-19 diagnostics, drugs, and 300 million doses of vaccines.
In another Operation Warp Speed contract, the U.S. Department of Health and Human Services on December 2 selected CVS Health for a pilot program designed to administer a limited supply of bamlanivimab to eligible COVID-19 patients at-risk of severe infection or complications from the virus.
Coram, the specialty pharmacy and infusion care business of CVS Health with more than 800 cetified nurses nationwide, will administer the intravenous therapy in patients’ homes or long-term care facilities. Coram agreed to administer 1,000 doses of monoclonal antibody therapies for COVID-19 in seven cities and their surrounding communities starting December 3, including Boston, Chicago, Cleveland, Los Angeles, Milwaukee, Minneapolis and Tampa, FL.
Eli Lilly joined Samsung Biologics on November 17 to announce a global, long-term manufacturing partnership for bamlanivimab and other Lilly COVID-19 antibody therapies. The value of the agreement was not disclosed, though the companies did say they entered into their partnership in May.
Since then, Samsung manufactured and delivered an initial supply of active pharmaceutical ingredients (API) meeting GMP and regulatory standards within five months of contract signing. The timeline for tech transfer was reduced dramatically to less than three months.
Emergency Use Authorization granted November 9 — The FDA on November 9 granted an emergency use authorization (EUA) to bamlanivimab as a treatment for adults and youths ages 12 years and older with mild-to-moderate COVID-19. The EUA allows for the distribution and emergency use of bamlanivimab for administration via a single intravenous infusion at the lowest IV dose studied, 700mg.
According to Lilly, bamlanivimab should be administered as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. Before patients can be treated with bamlanivimab under the EUA, they must weigh at least 40 kilograms (about 88 pounds) and be deemed at high risk for progressing to severe COVID-19 and/or hospitalization. That high-risk category includes adults who are ages 65 or older, or who have chronic medical conditions.
The FDA said it based the EUA on positive data from Lilly’s ongoing Phase II BLAZE-1 (NCT04427501), a randomized, double-blind, placebo-controlled study in 465 ambulatory (non-hospitalized) patients with recently diagnosed mild to moderate COVID-19. The trial assessed both bamlanivimab as monotherapy and in combination with etesevimab (also known as LY-CoV016), another Lilly antibody against COVID-19 that binds a different epitope in the SARS-CoV-2 spike region.
On October 27, the U.S. Army awarded a $312.5 million firm-fixed-price contract to Lilly (W911QY-21-C-0016) covering an unspecified quantity of bamlanivimab to be made at a Lilly production site in Indianapolis. Funds for the contract, awarded by U.S. Army Contracting Command, will come from the Coronavirus Aid, Relief, and Economic Security (CARES) Act, enacted March 27.
Eli Lilly and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) acknowledged in separate statements October 26 that the agency halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978). ACTIV-3 is designed to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.
The trial’s independent data safety monitoring board reviewed data October 26 at a scheduled meeting–data that suggested that bamlanivimab is unlikely to help hospitalized COVID-19 patients recover from the advanced stage of their disease.
Lilly said all other trials of LY-CoV555 were continuing, and noted that ACTIV-3 focused on hospitalized patients who were being treated with other drugs and were more severely ill than those in its other trials. The other trials include BLAZE-1; ACTIV-2 (NCT04518410), an NIH-sponsored study in recently diagnosed mild to moderate COVID-19 patients; and BLAZE-2 (NCT04497987), Lilly’s Phase III study of bamlanivimab for the prevention of COVID-19 in residents and staff at long-term care facilities.
Participants in the multicenter, adaptive, randomized, blinded, controlled trial were randomized to treatment with LY-CoV555 plus current standard of care (SOC), remdesivir plus current SOC, or placebo plus current SOC.
Eli Lilly confirmed to Reuters it received an “Official Action Indicated” (OAI) notice from the FDA after its inspectors found quality control problems at a company facility in Branchburg, NJ, that is gearing up to manufacture LY-CoV555.
The problems—including the deletion and improper auditing of data on the plant’s various manufacturing processes—were reported on October 13 based on a review of “heavily” redacted government inspection documents and three unnamed sources. The FDA told Reuters that it launched a “comprehensive remediation plan,” had increased staffing at the site, and was working “aggressively” to address concerns raised during the inspection. However, the agency declined to detail the manufacturing issues that led to the FDA action.
Earlier on October 13, Lilly said patient enrollment had been paused in the Phase III ACTIV-3 trial, citing an undisclosed safety concern. The trial had recruited 326 participants before the pause, which NIAID said was recommended by its independent data safety monitoring board after “an overall difference in clinical status between the group receiving LY-CoV555 and the group receiving saline placebo” was found during a planned interim analysis of safety data for the first 300 participants enrolled in the trial.
The board also recommended continuing to collect data, and following up with participants to assess their safety and the efficacy of the treatment.
Eli Lilly said October 8 it had committed to facilitating access to future Lilly therapeutic antibodies under development for to prevent and treat COVID-19 under an agreement signed with the Bill & Melinda Gates Foundation, as part of the COVID-19 Therapeutics Accelerator.
Commercial manufacturing of the antibodies will begin in April 2021 at the FUJIFILM Diosynth Biotechnologies facility in Denmark, where the Accelerator has reserved manufacturing capacity. The Gates Foundation partnered with Wellcome, and Mastercard to launch the Accelerator in order to accelerate development of and access to COVID-19 therapies.
A day earlier, Lilly said it will file an Emergency Use Authorization (EUA) application with the FDA for LY-CoV555 monotherapy in higher-risk patients recently diagnosed with mild-to-moderate COVID-19.
Lilly said it based its decision on a positive new interim analysis of data from the Phase II BLAZE-1 trial. The data showed that a combination of LY-CoV555 and LY-CoV016—another Lilly antibody that binds a different epitope in the SARS-CoV-2 spike region—reduced viral load, symptoms, and COVID-related hospitalization and ER visits.
A day later, Lilly announced additional BLAZE-1 data from an exploratory analysis which showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0%) vs. placebo (20.8%).
BLAZE-1 assessed the two neutralizing antibodies for the treatment of symptomatic COVID-19 in the outpatient setting. The combination cohort enrolled recently diagnosed patients with mild-to-moderate COVID-19, of which 112 were assigned to 2,800 mg of each antibody, while the other 156 patients were randomized to placebo.
The combination therapy met the trial’s primary endpoint by significantly reducing viral load at day 11, with most patients, including those receiving placebo, showing near complete viral clearance by day 11. The best outcome was in patients receiving the 2,800-mg dose, whose viral load was lowered by a factor of 3.4, according to a study published October 28 in The New England Journal of Medicine.
The study also showed that at day 29, the percentage of patients who were hospitalized with COVID-19 was 1.6% (5 of 309 patients) in the bamlanivimab group and 6.3% (9 of 143 patients) in the placebo group. The percentages in high-risk individuals was 3% for bamlanivimab patients and 10% for placebo patients.
Lilly added that the combination treatment reduced viral levels at day 3 and day 7, while also significantly reducing the time-weighted average change from baseline from day 1 to 11. An exploratory analysis showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0%) vs. placebo (20.8%).
The rate of COVID-related hospitalization and ER visits was lower for patients treated with combination therapy (0.9%) vs. placebo (5.8%), for an 84.5% relative risk reduction, similar to LY-CoV555 monotherapy.
Lilly said it expected to submit a request in November for an EUA for the combination therapy, pending clinical trial enrollment, once additional safety data accumulate and sufficient supply is manufactured. Lilly anticipated having data to support a BLA submission for combination therapy as early as second quarter 2021.
On September 17, Lilly joined Amgen in announcing a global antibody manufacturing collaboration designed to “significantly” increase the supply capacity available for Lilly’s potential COVID-19 therapies by quickly scaling up production of LY-CoV555 and/or any other antibodies developed alone or as combination treatments. The value of the agreement was not disclosed.
A day earlier, Lilly made headlines worldwide by announcing positive proof of concept data from an interim analysis of the Phase II BLAZE-1 trial showing a reduced rate of hospitalization for mild-to-moderate recently diagnosed COVID-19 patients treated with LY-CoV555. The trial’s pre-specified primary endpoint, change from baseline in viral load at day 11, was met at the middle of three dose levels studied (2800 mg), but not the other three groups studied (700 mg, 7000 mg, and placebo).
According to Lilly, most patients—including those randomized to placebo—showed near complete viral clearance by day 11. LY-CoV555 also improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points.
Another pre-specified endpoint, COVID-19-related hospitalization or ER visit, occurred in 1.7% (5/302) of LY-CoV555 patients, pooled across dose groups, compared to 6% (9/150) of placebo patients—a 72% risk reduction, Lilly said. Most study hospitalizations occurred in patients with underlying risk factors (age or BMI), suggesting a more pronounced treatment effect for patients in these higher-risk groups, a finding that Lilly said it will seek to confirm through ongoing studies.
The BLAZE-1 trial is enrolling a larger, confirmatory cohort of higher risk patients, testing the ability of the antibody combination to reduce the number of patients with persistently high viral load and reduce COVID-19 related hospitalizations.
In August, Eli Lilly launched BLAZE-2, a Phase III trial being conducted with NIAID, the COVID-19 Prevention Network (CoVPN), and several long-term care facility networks across the country.
BLAZE-2 is designed to study the efficacy and safety of LY-CoV555 for the prevention of SARS-CoV-2 infection and COVID-19 in up to 2,400 participants—both residents and staff at U.S. nursing homes and assisted living facilities. The study will enroll residents and staff who live or work at facilities that have had a recently diagnosed case of COVID-19, and who are now at a high risk of exposure. BLAZE-2 will assess whether a single dose of LY-CoV555 reduces the rate of SARS-CoV-2 infection through four weeks, as well as complications of COVID-19 through eight weeks.
To conduct the trial, Lilly has created customized mobile research units that include a custom retrofitted recreational vehicle (RV) to support mobile labs and clinical trial material preparation, along with a trailer truck that will deliver clinical trial supplies for an on-site infusion clinic. Lilly said it will deploy its mobile research unit fleet in response to outbreaks of the virus at long-term care facilities nationwide.
Also in August, Lilly launched ACTIV-3, which uses an adaptive two-stage protocol design intended to allow for modification to test additional experimental therapeutics, as well as flexibly allow novel therapeutics to enter at either stage 1 or stage 2. Should a treatment appear to be safe and effective in the initial stage after review by the DSMB, the treatment is to be advanced to stage 2 testing, where more volunteers are enrolled. If an investigational therapeutic is unsafe or not likely to be effective, it will be dropped.
The primary endpoint of ACTIV-3 is participants’ sustained recovery for 14 days after release form the hospital.
In June, Lilly and AbCellera said the first patients were dosed in a Phase I trial (NCT04411628) assessing the safety and tolerability of LY-CoV555 in patients hospitalized with COVID-19—what the companies called the world’s first study of a potential antibody treatments for the disease. The first patients were dosed at major medical centers in the U.S., including NYU Grossman School of Medicine and Cedars-Sinai in Los Angeles. Results are set for review later this month; if successful, LY-CoV555 will advance into broader efficacy trials, the companies said. The trial began less than a week after AbCellera completed a $105 million Series B financing, whose proceeds in part will fund R&D into LY-CoV555 and other antibody treatments the companies plan to develop.
In March, Lilly and AbCellera announced plans to partner to co-develop the most promising of 500+ unique fully human antibody sequences identified in a blood sample from one of the first U.S. patients to recover from COVID-19. AbCellera said it was tapping into the expertise of NIAID’s Dale and Betty Bumpers Vaccine Research Center, which was to identify the antibodies that bind the pandemic strain of SARS-CoV-2 the best.
AbCellera and Lilly committed to equally share initial development costs towards a treatment, after which Lilly has agreed to oversee all further development, manufacturing and distribution. If successful, Lilly will work with global regulators to bring a treatment to patients.
Globally, Lilly has joined a cross-industry collaboration and the Bill & Melinda Gates Foundation to accelerate the development, manufacturing and delivery of vaccines, diagnostics and treatments for COVID-19. The consortium of 17 life sciences companies, announced by the Foundation March 25, plans to will work with regulators and the World Health Organization to ensure promising studies are quickly scaled to help people worldwide.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: