Memorandum
February 25, 2022 Update: The 100th anniversary of insulin’s discovery this year has been accompanied with substantial development in basal insulins, rapid-acting insulins, glucose-responsive insulins, and pre-mixed insulin coformulations.
- Basal Insulin: In November 2021, the FDA granted Biocon/Viatris’ biosimilar insulin glargine Semglee an interchangeability designation, making it the first interchangeable and biosimilar insulin. Semglee is interchangeable with Sanofi’s Lantus, so it can be exchanged for Lantus at pharmacy counters without the need for prescriber input. Once-weekly insulins have been making progress in the pipeline with the 4Q20 phase 3 initiation for Novo Nordisk’s insulin icodec and Lilly’s planned phase 3 later this year for its basal insulin Fc (BIF). We are looking forward to seeing results from insulin icodec’s phase 3 program as trials reach completion throughout 2022. Once-weekly insulins have been generating high interest on the conference circuit due to their potential to simplify insulin therapy by enaling patients to take less frequent doses and to mitigate therapeutic inertia. In other exciting news, Oramed’s oral basal insulin initiated two phase 3 trials in type 2 diabetes – ORA-D-013-1 and ORA-D-013-2 – in January 2021, which are set to complete in September 2022 and November 2023, respectively.
- Rapid-acting insulin: Biocon/Viatris’ oral rapid acting insulin is set to complete a phase 1/2 study in 2022. Lilly’s Lyumjev (ultra-rapid acting insulin) was approved by the FDA for use in insulin pumps in August 2021, based on the PRONTO-Pump-2 trial. Adocia’s ultra-rapid BioChaperone Insulin Lispro is expected to initiate phase 3 trials in US, Europe, and China in 2022.
- Glucose responsive insulin: In June 2021, Novo Nordisk’s glucose responsive insulin (NN-1845) became the second candidate in this innovative class to complete a phase 1 trial. NN-1845 demonstrated proof-of-concept glucose sensitive properties and safety in both people with and without type 1 diabetes. The first glucose responsive insulin to complete a clinical trial was Merck’s MK-2640 in July 2016, though this candidate was discontinued due to negative phase 1 results. While Lilly does not yet list a glucose-responsive insulin in its pipeline, the company acquired Protomer along with its molecular engineered protein sensor technology in July 2021 to accelerate the development of glucose-responsive insulins.
- Insulin coformulations: Novo Nordisk’s once-weekly IcoSema (insulin icodec/GLP-1 semaglutide) initiated the phase 3 COMBINE-3 study in type 2 diabetes in November 2021. According to the company 4Q21 update two additional phase 3 trials are planned, for a total enrollment of 2,650 people with type 2 diabetes and completion expected in 2024. Novo Nordisk’s Xultophy (insulin degludec/GLP-1 liraglutide) was approved in China in October 2021, with a launch slated for 1H22. Sanofi’s Soliqua (insulin glargine/GLP-1 lixisenatide) read out SoliMix trial results at ADA 2021 with patient-reported outcomes presented at EASD 2021. Adocia’s M1Pram (pramlintide/human insulin analog) initiated a phase 2 trial in March 2021, which is expected to complete March 2022.
The table below includes an overview of the insulin competitive landscapes, covering basal insulin, rapid-acting insulin, glucose-responsive insulin, and other insulins. It includes all companies we are aware of with insulin candidates in development, though we acknowledge that it may be incomplete. We will continuously update the table as timelines change.
Basal Insulin
|
Sponsor |
Drug Name |
Type |
Status |
Timeline |
|
Lilly/BI |
Basaglar/ Abasaglar |
“Biosimilar” insulin glargine (not officially considered a biosimilar to Sanofi’s Lantus by the FDA, but close to identical) |
Approved and launched |
Launched in US on December 15, 2016 under terms of patent lawsuit settlement agreement with Sanofi |
|
Lilly |
Rezvolgar |
Biosimilar insulin glargine-aglr |
Approved |
Approved in US on December 20, 2021 |
|
Biocon/Viatris |
Semglee |
Biosimilar and interchangeable insulin glargine-yfgn |
Approved and launched |
Launched as first interchangeable biosimilar insulin in US in November 2021 – Received interchangeability designation by FDA July 2021 Launched in US as biosimilar August 2020 – Approved as biosimilar in US in June 2020 – CRL from the FDA August 2019; Form 483 from FDA July 2019 – CRL received from FDA June 2018 following September 2017 submission Launched in UK November 2019 – Approved by EMA in March 2018 Sanofi filed a patent infringement lawsuit against Mylan in October 2017 Launched in Japan (where it’s not partnered with Viatris) |
|
Oramed |
ORMD-0801 |
Oral insulin |
Phase 3 |
Initiated two phase 3 trials in T2D – ORA-D-013-1 and ORA-D-013-2 in January 2021, expected to complete in September 2022 and November 2023, respectively – In May 2022, Oramed granted patent for combination oral GLP-1 exenatide (ORMD-0901) and basal insulin (ORMD-0801) – European Patent Office granted Oramed a patent titled “Methods and Compositions for Treating NAFLD, Hepatic Steatosis, and Sequelae Thereof” in April 2022; not specified whether this patent involves ORMD-0801 – Initiated second phase 2 trial in NASH and T2D March 2021, expected to complete June 2022 (delayed from March 2022) – Initiated phase 2 trial in NASH and T2D November 2020, expected primary completion May 2022 (delayed from January 2022); completed enrollment March 2022, topline results expected 2H22 – Reported positive phase 2b optimal dose results February 2020; reported phase 2b results November 2019; phase 2b results reported July 2016 |
|
Novo Nordisk |
Insulin Icodec (NN1436) |
Once-weekly injectable acylated basal insulin |
Phase 3 |
According to 4Q21 update, some phase 3 results will be available in 2022 – Six-trial phase 3 ONWARDS program initiated in 4Q20 (ONWARD 1, 2, 3, 4, 5, and 6); ONWARD 2 to reach final complete February 28, 2022 – Three phase 2 trials completed against insulin glargine U100 – A head-to-head study presented at ADA 2020, a titration study published in April 2021, and study on switching to insulin icodec in published in April 2021 |
|
Novartis |
Undisclosed |
Biosimilar insulin glargine |
Phase 3 |
In October 2021, proposed biosimilar insulin glargine completed phase 3 trial – Phase 1 data from three proposed biosimilar insulins (glargine, lispro, and aspart) were presented at ADA 2021 In December 2018, announced agreement with Gan & Lee split development/ commercialization responsibilities – Novartis to commercialize biosimilar insulin glargine, biosimilar insulin lispro, and biosimilar insulin aspart in the US, EU, Switzerland, Japan, South Korea, Canada, Australia, and New Zealand – Gan & Lee takes responsibility for manufacturing and development |
|
Lilly |
Basal Insulin-Fc (BIF, LY3209590) |
Once-weekly basal insulin |
Phase 3 |
4Q21 update confirms BIF to enter five phase 3 trials (QWINT program) in 2022, four in type 2 diabetes and one in type 1 diabetes – In October 2021, completed two phase 2 trials in insulin-naïve patients with T2D and in people with T1D, results not released yet – Phase 2 data presented at ENDO 2021 and ADA 2021; movement into phase 2 announced during 2018 Investor Day |
|
PhaseBio |
Insumera (PE0139) |
ELPylated once-weekly basal insulin (human insulin fused with elastin-like polypeptide, aka. ELP) |
Phase 2 |
Insumera is not listed on PhaseBio’s pipeline – Completed a phase 2 trial in type 2 diabetes in November 2016, no results shared – Reported positive phase 1 data in type 2 diabetes at ADA 2015 |
|
Novo Nordisk |
FSI965 (Insulin 965) |
Next-generation basal insulin |
Phase 1 |
Phase 1 trial against insulin glargine completed December 2021 – In August 2020, completed phase 1 trial in type 2 diabetes, results not released yet – In December 2019, completed a phase 1 study in people with T1D, results not released yet |
|
Lannett/HEC |
Undisclosed |
Biosimilar insulin glargine |
Phase 1 |
Pivotal trial initiated March 2022, expected completion with BLA filing early 2023 and potential launch early 2024 – FDA completes IND review January 2022, pivotal trial to commence March 2022 – First clinical trial announced June 2019 – Positive phase 1 results released December 2019 |
|
Hanmi Pharmaceuticals |
LAPSInsulin / LAPSInsulin Analog (HM12460A / HM12470) |
Once-weekly basal insulin (Fc fusion insulin) |
Phase 1 |
No recent updates – PK/PD data published December 2017 – Poster on mechanism presented at ADA 2016 – Sanofi acquired candidate from Hanmi in November 2015, but was returned in December 2016 due to downsizing of licensing deal |
|
AstraZeneca |
Undisclosed |
Once-weekly basal insulin (single-chain insulin molecule fused to Fc region) |
Preclinical |
In June 2019, published preclinical data in Diabetes |
|
Rezolute Bio (f.k.a. AntriaBio) |
AB101 |
PEGylated once-weekly insulin |
Phase 1/Discontinued |
CEO stated candidate would only proceed if a partnership is made with a company that can optimize AB101’s formulation; – Follows mixed phase 1 topline results announced in Jan 2019; phase 1 trial initiated July 2017 – Preclinical data for presented at ADA 2015 – IND submitted to FDA June 2017 |
|
Merck |
Lusduna Nexvue |
Biosimilar insulin glargine |
Discontinued |
Discontinued for commercial reasons in October 2018 following tentative FDA approval granted July 2017 – Full approval contingent on resolution of Sanofi’s patent infringement lawsuit, filed September 2016 – Phase 3 data reported at ADA 2016 |
|
Lilly |
Once-weekly insulin |
Discontinued |
Discontinued |
|
|
Arecor |
Insulin glargine with improved thermostability |
Biosimilar insulin glargine |
Discontinued |
Preclinical program removed from company website |
|
Arecor |
Ultra-long-acting insulin glargine |
Biosimilar insulin glargine |
Discontinued |
Preclinical program removed from company website |
Rapid-Acting Insulin
|
Sponsor |
Drug Name |
Type |
Status |
Timeline |
|
Novo Nordisk |
Fiasp |
Faster-acting insulin aspart (Novo Nordisk’s NovoLog) |
Approved and launched |
EMA label expansion to include children and adolescents ≥1 in August 2019 – FDA approval in September 2017 after initial CRL in October 2016; – EMA approval in January 2017 |
|
Sanofi |
Admelog (SAR342434) |
Biosimilar insulin lispro (Lilly’s Humalog) |
Approved and launched |
US launch April 2018 following FDA approval in December 2017 – EMA approval in July 2017 – SORELLA 1 trial presented at ADA 2016; SORELLA 2 trial presented at ADA 2017, along with one-year SORELLA 1 data |
|
Lilly |
Lyumjev |
Ultra-rapid-acting insulin |
Approved and launched |
Approved by FDA for use in insulin pumps in August 2021, based on PRONTO-Pump-2 trial – Approved by FDA in June 2020; submitted to FDA in type 1 and type 2 in 3Q19 – Full PRONTO-T1D and full PRONTO-T2D results presented at ADA 2019 – Topline results for PRONTO-T1D and PRONTO-T2D announced October 2018; phase 3 trials began 3Q17; phase 2 data presented at ADA 2017 |
|
Sanofi |
Truvelog |
Ultra-rapid-acting insulin aspart (biosimilar/follow-on to NovoLog) |
Approved and launched |
Granted EU marketing authorization July 2020 and launched in several European countries in 2020 – Received positive CHMP opinion May 2020 – Submitted to EMA in May 2019 US strategy was “under consideration” in 4Q18, but portfolio streamlining goals set out in late 2019 likely led to not pursuing US approval GEMELLI X (PK comparison with NovoLog) completed July 2020 – GEMELLI 1 (open-label vs. Novo Nordisk’s NovoLog) completed January 2019 – GEMELLI P (comparison to NovoLog as continuous subcutaneous infusion) completed October 2018 Added to pipeline in 4Q16 |
|
Biocon/Viatris |
Undisclosed |
Biosimilar insulin aspart (Novo Nordisk’s NovoLog) |
In submission in US/ approved in EU, Canada, and emerging markets |
Received FDA CRL on January 7, 2022 – In May 2022, Securities and Exchange Board of India allows for important and marketing of biosimilar insulin aspart in India without requiring a phase 3 trial but requiring a phase 4 post-marketing trial – In September 2021, FDA inspection leads to six observations to be addressed, Biocon submitted a CAPA in response Received EU marketing authorization in 1Q21; – In 4Q20, received positive CHMP opinion and was approved in Malaysia |
|
Adocia/Tonghua Donbao |
BioChaperone (BC) Insulin Lispro U100 and U200 |
Ultra-rapid-acting insulin lispro (Lilly’s Humalog) |
Phase 3 |
In May 2022, first patient dosed in phase 3 program enrolling 1,300 patients with type 1 or 2 diabetes in China – Phase 3 initiation in US, Europe, and China expected in 2022, according to January 2022 Adocia pipeline summary – In March 2019; initiated phase 2/3 investigating BC lispro using Beta Bionics’ iLet AID system – Topline results for phase 1 comparing BC insulin lispro to Humalog released January 2021 – Data presented at ADA 2017 – Phase 1b pump study completed November 2016 Partnered with Tonghua Dongbao to commercialize in China and other Asian and Middle Eastern countries in April 2018 Lilly terminated partnership January 2017 |
|
Diasome |
HDV Insulin Lispro |
Liver-targeted insulin lispro (Lilly’s Humalog) |
Phase 2 |
Phase 2 OPTI-1 study results read out at ADA 2020 –Announced positive topline results February 2020 – Completed enrollment June 2019, and presented Phase 2 ISLE-1 trial completed June 2018, results published September 2019 In July 2017, received $30 million from Medicxi and JDRF T1D Fund, among others, to support advancements |
|
Biocon/Viatris |
Insulin Tregopil |
Oral insulin |
Phase 1/2 |
Phase 1/2 trial ongoing in type 1 diabetes Completed phase 2/3 study in type 2 diabetes in 2019, but failed to significantly reduce A1c over 24 weeks; – PK/PD data presented at ADA 2018 – Positive phase 1 results in January 2016 – In September 2017, JDRF funded phase 2 dose optimization trial vs. insulin aspart in Europe |
|
Arecor |
Ultra Rapid Acting Insulin (AT247) |
Ultra-rapid-acting insulin |
Phase 1 |
Phase 1 (compared to NovoLog and Fiasp) initiated January 2022, exp. completion September 2022 Positive phase 1 results released in December 2019 First patient dosed in EU PK/PD phase 1 in May 2019 |
|
Arecor |
Ultra-concentrated rapid acting insulin (AT278) |
U1000 stable, rapid-acting insulin formulation |
Phase 1 |
Phase 1 trial (compared to NovoRapid) initiated December 2020, completed June 2021, positive topline results released September 2021 Preclinical program completed in January 2018 Funded by JDRF in July 2016 |
|
Novartis |
Undisclosed |
Biosimilar insulin lispro and aspart |
Phase 1 |
Phase 1 data from three proposed biosimilar insulins ( glargine, lispro, and aspart) were presented at ADA 2021 In December 2018, announced agreement with Gan & Lee to split responsibilities for multiple biosimilar rapid-acting insulins – Novartis to commercialize biosimilar insulin glargine, biosimilar insulin lispro, and biosimilar insulin aspart in the US, EU, Switzerland, Japan, South Korea, Canada, Australia, and New Zealand – Gan & Lee takes responsibility for manufacturing and development |
|
Thermalin |
T-1123 |
Rapid-acting, ultra-rapid and concentrated (U500) analog |
Preclinical |
Plans to start clinical trials in 2022 In September 2020, received a $3 million direct-to-phase 2 grant by the NIH In August 2019, selected T-1123 as a preclinical candidate, based on preclinical studies showing comparable efficacy with Novo Nordisk’s U-100 Fiasp |
|
Biocon/Viatris |
Undisclosed |
Biosimilar insulin lispro (Lilly’s Humalog) |
Discontinued |
No updates as of February 2022, suggesting discontinuation – Phase 1 trial of prandial oral insulin vs. insulin lispro injection terminated due to “unanticipated bioanalytical issue” |
|
Novo Nordisk |
PI406 (NN1406) |
Liver-preferential prandial insulin analog |
Discontinued |
Program terminated in 1Q18 after phase 1 trial results |
Glucose-Responsive Insulins
|
Sponsor |
Drug Name |
Type |
Status |
Timeline |
|
Novo Nordisk |
NN-1845 |
Synthetic glucose-binding protein (lectin-based) attached to NN insulin |
Phase 1 |
In June 2021, completed phase 1 trial in people without diabetes and people with type 1 diabetes, demonstrating proof-of-concept glucose sensitive properties and safety in both healthy participants and people with type 1 diabetes Glucose-binding proteins acquired from Ziylo in August 2018 |
|
Gubra |
Undisclosed |
Circulating locked insulin depot w/ basal and prandial properties |
Preclinical |
As of February 2022, listed in preclinical stage in pipeline Announced with JDRF funding in June 2018 |
|
Lilly |
Undisclosed |
Bi-directional antibody-based insulin (Glycostasis) or molecular engineered protein sensor (Protomer) |
Preclinical |
Lilly acquired Protomer in July 2021, and Protomer was funded by JDRF GRI Grand Challenge Prize and a JDRF/Sanofi grant Glycostasis technology acquired by Lilly in February 2016 |
|
UNC/NC State |
Smart insulin patch |
Undisclosed |
Preclinical |
Positive preclinical data presented at ADA 2016 Funded by ADA Pathway and JDRF/Sanofi grants |
|
MIT/University of Utah |
Undisclosed |
Synthetic glucose-responsive insulin |
Preclinical |
Positive preclinical results published February 2015 Funded by JDRF/Sanofi grant |
|
Monash University |
Undisclosed |
Glucose-sensing nanoparticles |
Preclinical |
Funded by JDRF/Sanofi grant |
|
Calibr |
Undisclosed |
Antibody-based, reversible intramolecular switch (“case four”) |
Preclinical |
Showcased at JDRF Mission Summit in 2016 |
|
Sensulin |
Undisclosed |
Biodegradable hydrogel using native insulin (“case one”) |
Preclinical |
Company website says work on glucose responsive insulin is active, but no updates over the past several years Featured at Lyfebulb Social Club in June 2015 |
|
Thermalin |
Undisclosed |
Insulin modified with tailored carbohydrates targeting lectins |
Preclinical |
While no program is mentioned on the company website, Thermalin and its founder Dr. Michael Weiss were involved in a July 2021 study of a metabolite-dependent insulin-receptor activation. |
|
Biodel |
Undisclosed |
Glucose-coupled, pH-controlled dissolution of insulin |
Discontinued |
Biodel no longer a company |
|
Merck |
MK-2640 |
Insulin saccharide conjugate that binds to insulin receptor or mannose receptor, depending on glucose concentration |
Discontinued |
Discontinued following negative phase 1 results – Full phase 1 results published September 2018, finding no glucose-dependent change in MK-2640 clearance in people with type 1 diabetes – Completed phase 1 trial in July 2016 |
Other Insulins (Pre-mixed, Human)
|
Sponsor |
Drug Name |
Type |
Status |
Timeline |
|
Novo Nordisk |
Xultophy |
Once-daily injectable insulin degludec and GLP-1 liraglutide coformulation |
Approved in multiple geographies |
In October 2021, Xultophy was approved in China with a launch slated for 1H22 In February 2019, FDA expands indication, removing the requirement patients already be taking basal insulin or Victoza – FDA approval November 2016; May 2016 FDA AdCom Meeting Approved in Canada April 2018 Readout of DUAL program at ADA 2015 |
|
Sanofi |
Soliqua |
Once-daily injectable insulin glargine and GLP-1 lixisenatide coformulation |
Approved in US and EU |
SoliMix trial readout at ADA 2021 with patient-reported outcomes presented at EASD 2021 In February 2019, FDA expands indication, removing requirement that patients already be on basal insulin or Adlyxin – EU approval January 2017 – FDA approval November 2016 – FDA AdComm Meeting May 2016 – Positive phase 3 results from LixiLan-L presented at EASD 2015 – Positive topline phase 3 results from LixiLan-O trial July 2015 |
|
Biocon/PiSA |
Rh-insulin |
Recombinant human insulin |
Approved in “most of world” / regulatory submission in US |
In May 2022, publication of PK/PD results from RHINE-3, showing equivalence between Biocon’s biosimilar insulin 70/30 with Lilly’s Humulin 70/30 – In January 2022, publication of PK/PD results from RHINE-1 study showing equivalence to Lilly’s Humulin, which Biocon plans to use to seek FDA biosimilar approval, according to 4Q21 update – Introduced rh-Insulin initiation kits to enable smooth transition from OAD to insulin in 3Q21 – According to 3Q20 update, BLA under review by FDA under 351(k) pathway Launched in the Philippines under the “10 cents program” in 3Q20 Partnership formed in March 2016 Biocon already markets the product in >60 countries including India and emerging markets |
|
Novo Nordisk |
IcoSema |
Once-weekly injectable insulin icodec and GLP-1 semaglutide coformulation |
Phase 3 |
Phase 3 (COMBINE-3) in type 2 diabetes initiated November 2021, est. primary completion September 2023 According to 4Q21 update, two additional phase 3 trials are planned, for a total enrollment of 2,650 people with type 2 diabetes and completion expected in 2024 Phase 2 results are expected in 2022, according to 4Q21 update Completion of phase 1 trial announced in 4Q19 update |
|
Adocia |
M1Pram |
Injectable pramlintide and human insulin analog coformulation |
Phase 2 |
Study presented at EASD 2021 showed TIR and body weight improvement compared to insulin asapart Phase 2 trial launched March 2021, exp. completion March 2022 Positive topline results from phase 1b extension released September 2020 – Positive topline phase 1 results shared in April 2020 – Positive topline phase 1 results shared April 2019 |
|
Xeris |
XP-3924 |
Pramlintide and insulin coformulation |
Phase 2 / Looking for partner / discontinued internal development |
Based on 4Q20 and 3Q21 updates, Xeris has designed a phase 3 trial and intends to seek a development and commercialization |
|
Adocia |
BioChaperone Combo |
Insulin glargine (Sanofi’s Lantus) & insulin lispro (Lilly’s Humalog) |
Phase 1 |
In April 2022, German regulatory authorities approved three clinical studies, which will be used to support phase 3 trials in China Positive results from phase 1b study in type 2 diabetes announced June 2017 Phase 1 data presented at ADA 2016 Licensed to Tonghua Dongbao in China + other countries |
|
Novo Nordisk |
NNC0472-0147 |
Long-acting insulin analogue (Insulin 147) & PCSK9 inhibitor (undisclosed) |
Phase 1 |
Completed a phase 1 trial against insulin glargine in September 2020, results not yet posted |
|
TD Solutions (aka. HypoSpray Pharma) |
Levellor HypoSpray Insulin |
Human insulin U100 and U200, applied to skin |
Phase 1 |
Phase 1 trial initiated March 2021, completed January 15, 2022, results not yet released Announced in May 2018 |
|
Hanmi Pharmaceuticals |
LAPSInsulin Combo (HM14220) |
Combination once-weekly GLP-1 and once-weekly insulin analog |
Preclinical |
Included in Hanmi’s metabolic disease pipeline as of February 2022 |
|
Adocia |
HinsBet U100 |
BioChaperone human insulin |
Discontinued |
Not listed on company pipeline Phase 1/2 study completed August 2016 Company intends to license phase 3-ready candidate to regional player in emerging markets |
– Ashwin Chetty, Katie Mahoney, and Kelly Close