DURECT CORPORATION

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DURECT CORP Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q)

08/05/2022 | 04:05pm EDT

This Management's Discussion and Analysis of Financial Condition and Results of Operations for the three and six months ended June 30, 2022 should be read in conjunction with (i) our unaudited condensed financial statements and related notes appearing elsewhere in this Quarterly Report on Form 10-Q and (ii) our annual report on Form 10-K for the year ended December 31, 2021 filed with the Securities and Exchange Commission ("SEC") as well as the "Risk Factors" section included elsewhere in Part II, Item IA of this Quarterly Report on Form 10-Q. References to the "Company," "DURECT," "we," "us" and "our" refer to DURECT Corporation.



Overview

We are a biopharmaceutical company advancing novel and potentially lifesaving investigational therapies derived from our Epigenetic Regulator Program. Larsucosterol (also known as "DUR­928"), a new chemical entity in clinical development, is the lead candidate in our Epigenetic Regulator Program. An endogenous, orally bioavailable small molecule, larsucosterol has been shown in both in vitro and in vivo studies to play an important regulatory role in lipid metabolism, stress and inflammatory responses, and cell death and survival. We are developing larsucosterol for alcohol-associated hepatitis ("AH"), a life-threatening acute liver condition with no approved therapeutics and a 28-Day and 90-Day historical mortality rate of 20%-26% and 29%-31%, respectively. After completing a Phase 2a trial in which 100% of AH patients treated with larsucosterol survived the 28-Day study period, we are now conducting a ~300-patient, double-blind, placebo-controlled Phase 2b clinical trial called AHFIRM (trial in AH to evaluate saFety and effIcacy of laRsucosterol treatMent). Through our AHFIRM trial, we are evaluating larsucosterol's potential to reduce mortality or liver transplantation compared to a placebo with or without steroids at the investigators' discretion. Currently we anticipate dosing the last patient in the AHFIRM trial in mid-2023. If the AHFIRM trial is successful, it may support a New Drug Application ("NDA") filing and we may decide to develop our own commercial, sales and marketing organization. We have also investigated larsucosterol in patients with nonalcoholic steatohepatitis ("NASH") with encouraging results in a Phase 1b clinical trial and are considering further development for this and other indications.

In addition to our Epigenetic Regulator Program, we developed a novel and proprietary post-surgical pain product called POSIMIR that utilizes our innovative SABER platform technology to enable continuous sustained delivery of bupivacaine, a non-opioid local analgesic, over three days in adults. In February 2021, POSIMIR received U.S. FDA approval for post-surgical pain reduction for up to 72 hours following arthroscopic subacromial decompression. In December 2021, we entered into a license agreement with Innocoll Pharmaceuticals Limited, pursuant to which the Company granted to Innocoll an exclusive, royalty-bearing, sublicensable right and license to develop, manufacture and commercialize POSIMIR in the United States. Under the agreement, DURECT will earn low to mid double-digit royalties from net sales of POSIMIR and is eligible to receive up to an additional $132 million in milestone payments.

NOTE: POSIMIR® is a trademark of Innocoll Pharmaceuticals, Ltd. in the U.S. and a trademark of DURECT Corporation outside of the U.S. SABER®, CLOUD™, ORADUR™ and ALZET ® are trademarks of DURECT Corporation. Other trademarks referred to belong to their respective owners. Full prescribing information for POSIMIR, including BOXED WARNING and Medication Guide can be found at www.posimir.com. Full prescribing information for PERSERIS, including BOXED WARNING and Medication Guide can be found at www.perseris.com.



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As a result of the assignment of certain patent rights, DURECT also receives single digit sales-based earn-out payments from U.S. net sales of Indivior UK Limited ("Indivior")'s PERSERIS™(risperidone) drug for schizophrenia and single-digit royalties from net sales of Orient Pharma Co., Ltd. ("Orient Pharma")'s Methydur Sustained Release Capsules (Methydur) for the treatment of attention deficit hyperactivity disorder (ADHD) in Taiwan. We also manufacture and sell ALZET osmotic pumps used in laboratory research and have several early-stage development programs with corporate collaborators on terms which typically call for our collaborator to fund all or a substantial portion of future development costs and then pay us milestone payments based on specific development or commercial achievements plus royalties on product sales.

Additional details of these programs and related strategic agreements are contained in our annual report on Form 10-K for the year ended December 31, 2021 and in Note 2 of the financial statements included in Item 1 above.

Epigenetic Regulator Program and New Chemical Entities

Epigenetic regulation influences the expression of genes through the silencing or initiation of gene activity without modifying the DNA sequence. For instance, methylation of cytosine nucleotides in promoter regions of DNA, facilitated by DNMTs, will generally result in downregulation of gene expression, while demethylation generally results in upregulation. DNA methylation/demethylation can thus regulate the expression of relevant genes, especially clusters of master genes that further modulate crucial cellular activities.

DURECT's Epigenetic Regulator Program involves a multi-year collaborative effort with the Department of Internal Medicine at Virginia Commonwealth University ("VCU"), the VCU Medical Center and the McGuire VA Medical Center. The knowledge base supporting this program is a result of more than 30 years of lipid research by Shunlin Ren, M.D., Ph.D., Professor of Internal Medicine at the VCU Medical Center. The lead compound from this program, larsucosterol, is an endogenous sulfated oxysterol, which acts as an epigenetic regulator. Under a license with VCU, we hold the exclusive royalty-bearing worldwide right to develop and commercialize larsucosterol and related molecules discovered in the program.

In March 2021, a peer-reviewed research paper proposed mechanism of action of larsucosterol was published in The Journal of Lipid Research. The publication showed that larsucosterol (referred to in the paper as "25HC3S") bound to and inhibited the activities of DNA methyltransferases (DNMTs) 1, 3a and 3b, enzymes that add methyl groups to DNA (a process called "DNA methylation"), as well as reduced DNA hypermethylation. DNMT1 and 3a have been shown to be over-expressed in the livers of patients with severe AH. As such, by inhibiting DNMT activities, larsucosterol may inhibit DNA hypermethylation, thereby modulating the expression of genes and pathways that are involved in crucial cellular activities, including those associated with cell death, stress response, and lipid biosynthesis. These modulations may lead to improved cell survival, reduced lipid accumulation or lipotoxicity, minimized inflammation, and enhanced liver regeneration, as has been observed in various in vivo animal models and in results from our completed clinical trials in AH and NASH patients.

The biological activity of larsucosterol has been demonstrated in over a dozen different animal disease models involving three animal species. Some of these models represent acute organ injuries (e.g., LPS-induced endotoxin shock, drug-induced acute oxidative stress injury, ischemic-reperfusion-induced kidney and brain injury, and some represent chronic metabolic disorders (e.g., diabetes-NASH and NAFLD).

Our major product research and development efforts for larsucosterol are described in the following table:



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In pharmacokinetic ("PK") and toxicology studies conducted in mice, rats, rabbits, dogs, minipigs and monkeys, larsucosterol has been found to be well tolerated and safe by all routes of administration tested to date. These results support the use of larsucosterol in completed and ongoing human safety, PK, proof-of-concept, and efficacy trials. The chronic toxicity of larsucosterol was further assessed in a 6-month oral study in rats and in a 9-month oral study in dogs. These studies support the use of larsucosterol in long duration human trials.

Acute Organ Injury Program with Injectable larsucosterol

Market Opportunity. Alcohol-associated hepatitis (also called "alcoholic hepatitis" or "AH"), an acute form of alcohol-associated liver disease, is associated with long-term heavy intake of alcohol and often occurs after a recent period of increased alcohol consumption. AH is typically characterized by recent onset jaundice and hepatic failure. AH was associated with approximately 137,000 U.S. hospitalizations in 2019 according to the available data published for the year. A retrospective analysis of 77 studies published between 1971 and 2016, which included data from a total of 8,184 patients, showed the overall mortality from AH was 26% at 28 days, 29% at 90 days and 44% at 180 days. A subsequent global study published in December 2021, which included 85 tertiary centers in 11 countries across 3 continents, prospectively enrolled 2,581 AH patients with a median MELD score of 23.5, reported mortality at 28 and 90 days of 20% and 30.9% respectively.

A Model of End-Stage Liver Disease ("MELD") score is a commonly used scoring system to assess the severity and prognosis of AH patients. There are no FDA approved therapies for AH and stopping alcohol consumption is necessary, but frequently not sufficient for recovery in many moderate and severe patients. Corticosteroids do not improve survival at 90 days or one year, and have demonstrated an increased risk of infection. In addition, fewer than 50% of AH patients are eligible for corticosteroids. According to a recent study, the healthcare costs associated with treating hospitalized AH patients and their length of hospital stay are significant.


   Each hospitalization      Average length of stay     Average total charges
episode with AH diagnosis                                during hospital stay
    for patients who:
     Died during the                 9 days                    $147,000
     hospitalization
     Were discharged                 6 days                    $53,000

Marlowe, N., Lam, D., Krebs, W., Lin, W. & Liangpunsakul, S. (2022) Prevalence, co-morbidities, and in-hospital mortality of patients hospitalized with alcohol-associated hepatitis in the United States from 2015 to 2019. Alcoholism: Clinical and Experimental Research.

The rate of AH patients undergoing liver transplantation has been increasing in recent years, although the total number of such transplants is still relatively small. Average charges for a liver transplant exceed $875,000, and patients require lifelong immunosuppressive therapy to prevent organ rejection.

Clinical Program. In 2019, we completed a Phase 2a clinical trial evaluating safety and PK of intravenously infused larsucosterol in patients with moderate and severe AH. This was an open label, dose escalation (30 mg, 90 mg and 150 mg), multi-center U.S. study, designed to be conducted in two sequential parts. Part A included patients with moderate AH and Part B included patients with severe AH. Severity of AH was determined by MELD scores with moderate defined as MELD 11-20 and severe as MELD 21-30.

In this Phase 2a trial, dose escalation was permitted following review of safety and PK results of the prior dose level by a Dose Escalation Committee. The target number of patients for the study was 4 per dose group. Final enrollment included 19 patients with moderate (7 of 19) and severe AH (12 of 19), who received larsucosterol intravenously at 30 mg, 90 mg, or 150 mg doses. Eight patients (four moderate and four severe) were dosed at 30mg, seven patients (three moderate and four severe) were dosed at 90mg and four patients (all severe) were dosed at 150mg. After being discharged on Day 2, one patient did not return for the scheduled Day 7 and Day 28 follow-up visits; therefore Lille, bilirubin and MELD data reported below are based on 18 patients. The objectives of this study included assessment of safety, PK and pharmacodynamic signals, including liver biochemistry, biomarkers, and prognostic scores, including the Lille score, following larsucosterol treatment.

In November 2019, the results from this Phase 2a clinical trial of larsucosterol in AH were presented as a late-breaking oral presentation at The Liver Meeting®. The study summary results were also selected for inclusion in the 'Best of The Liver Meeting' presentation in the alcohol-related liver disease category.


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All 19 patients treated with larsucosterol in this trial survived the 28-day follow-up period and there were no drug-related serious adverse events. Using an alternative measure of AH severity to MELD, Maddrey's Discrimination Function ("DF"), 15 of the 19 patients had DF scores of 32 or greater, indicating that they had severe AH. Patients treated with larsucosterol had a statistically significant reduction from baseline in bilirubin at Day 7 and 28 and MELD at Day 28. Lille scores, described below, were also statistically significantly lower than those from a well-matched group of patients in a contemporary trial as well as several published historical controls. 74% of all larsucosterol treated patients and 67% of those with severe AH were discharged from the hospital within 4 days after receiving a single dose of larsucosterol.

Lille

Lille scores are used in clinical practice to help determine the prognosis and response of AH patients after 7 days of treatment. The lower the Lille score, the better the prognosis. Patients with a Lille score below 0.45, treatment responders, have a six-month survival rate of 85% compared to those with Lille scores above 0.45, who have only a 25% six-month survival rate. The chart below shows the Lille scores for individual AH patients treated with larsucosterol plotted as a function of their baseline MELD scores. In our study, the median Lille score for patients treated with larsucosterol was 0.10. The median Lille score among a cohort of 15 patients treated with standard of care at the University of Louisville ("UL") was 0.41 (shown as historical control).



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    1) Our advisor, Dr. Craig McClain from UL, shared anonymized data from his
       study, in which 15 AH patients with initial MELD scores ranging from 15-30
       received either supportive care alone (n=8 moderate AH patients) or
       supportive care with corticosteroids (n=7 severe AH patients). Two of the
       UL control patients died by Day 28.


    2) One patient in the larsucosterol (also known as "DUR-928") group did not
       return for the Day 7 or 28 visit. All 19 patients, including this one,
       treated with larsucosterol in this trial survived the 28-Day follow-up
       period.


    3) Lille scores in the larsucosterol group were significantly lower than that
       of the UL patients (p=0.01; Wilcoxon's Rank Sum Test).


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As shown in the table below, all patients in the 30 mg and 90 mg larsucosterol dosing groups were treatment responders based on their Lille scores, regardless of disease severity by DF, MELD, or baseline serum bilirubin levels. 89% of the overall larsucosterol patient population (16 of 18) were treatment responders based on Lille. Patients with severe AH, as defined by DF ?32 or MELD 21-30, and baseline serum bilirubin above 8 mg/dL, had similarly high response rates to larsucosterol treatment.




     AH Patient Category         n1  Responders        Lille
                                    (Lille<0.45) Median (Quartile)
All Patients2                    18     89%      0.10 (0.04, 0.20)

30 mg or 90 mg larsucosterol 3 14 100% 0.05 (0.04, 0.19) DF?32 (SAH)2, 4

                  15     87%      0.19 (0.05, 0.22)

30 mg or 90 mg larsucosterol 3 11 100% 0.12 (0.05, 0.19) MELD 21-302

                      12     83%      0.19 (0.11, 0.25)

30 mg or 90 mg larsucosterol 3 8 100% 0.19 (0.10, 0.19) Baseline bilirubin >8mg/dl2 11 82% 0.10 (0.05, 0.20) 30 mg or 90 mg larsucosterol 3 8 100% 0.10 (0.05, 0.19)


  1) One patient did not return for Day 7 and 28 visits.


  2) Including patients receiving 30 mg, 90 mg and 150 mg of larsucosterol.


  3) Excluding patients receiving 150 mg of larsucosterol.


    4) DF is calculated using the patient's prothrombin time and serum bilirubin
       level. DF was introduced in 1978 as a predictor of significant mortality
       risk for AH patients. A DF?32 identified AH patients with a 30-Day
       mortality rate of ?50%.


The Lille scores of patients treated with larsucosterol in this trial were also significantly lower than several selected published historical studies (Hepatology 2007, 45:1348-1354; Gut 2011, 60:255-260), in which patients had similar baseline bilirubin, albumin, creatinine, prothrombin time and DF scores, and were treated with standard of care with or without corticosteroids. Due to the historical nature of these studies, such comparisons should be taken cautiously.

A sub-group analysis was conducted to compare severe AH patients in the 30 mg and 90 mg dosing groups (n=8) with well-matched severe AH patients (n=13) who received corticosteroids for 28 days in a contemporaneous study at UL. Patients shown in the chart below in the UL steroid group had a mean baseline MELD of 24.46 and mean baseline Maddrey's DF score of 62.98. The 8 patients in the larsucosterol group had baseline mean MELD of 24.50 and mean baseline Maddrey's DF score of 61.25. All patients treated with larsucosterol survived the 28-Day follow up period, while 3 of the 13 patients (23%) in the UL steroid group died within the first 28 days.



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The steroid group in the above graph includes the 7 severe AH patients treated with steroids from the UL group shown in the MELD vs Lille graph above plus an additional 6 severe AH patients subsequently treated in the UL study.



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Bilirubin

Bilirubin is formed by the breakdown of red blood cells in the body. The level of total bilirubin in the blood is an indication of how the liver is functioning. Elevated bilirubin levels usually signify liver dysfunction and disease. In this trial (shown in the chart below), patients treated with larsucosterol had a significant early reduction from baseline in bilirubin by Day 7. Patients with more elevated bilirubin at baseline (serum bilirubin >8 mg/dL) had a median reduction from baseline of 25% by Day 7 and 48% by Day 28.




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*p<0.05 compared to baseline (Wilcoxon's Signed Rank Test)

As discussed above, MELD is another commonly used scoring system used to assess the severity and prognosis of AH patients. Patients with MELD scores of 11-20 are classified as having moderate AH and patients with MELD scores of 21-30 are classified as having severe AH. As with Lille scores, the lower the MELD score, the better the prognosis for the AH patient. In this trial (shown in the chart below), the median reduction from baseline in MELD among all larsucosterol treated patients was >2 points and among those with baseline bilirubin levels >8 mg/dL was 5 points by Day 28.




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*p<0.05 compared to baseline (Wilcoxon's Signed Rank Test)


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MELD is calculated based on (a) bilirubin, (b) serum creatinine (sCr), and (c) International Normalized Ratio (INR), which is a measure of prothrombin time.

Safety and Pharmacokinetics

In the Phase 2a study of larsucosterol in AH, larsucosterol was well tolerated at all doses tested. There were no drug-related serious adverse events and only three adverse events designated as possibly or probably related to larsucosterol: one occurrence of moderate generalized pruritus, one mild rash and one grade two alkaline phosphatase elevation. There were no discontinuations, early withdrawals or termination of study drug or study participation due to adverse events. All patients treated with larsucosterol survived through the 28-Day follow-up period. Drug exposures were dose proportional and were not affected by the severity of the disease.

In December 2020, we announced that the FDA had granted larsucosterol Fast Track Designation for the treatment of AH. The FDA grants Fast Track Designation to facilitate development and expedite the review of therapies with the potential to treat a serious condition where there is an unmet medical need. A therapeutic that receives Fast Track Designation may benefit from early and frequent communication with the agency in addition to a rolling submission of the marketing application, with the objective of getting important new therapies to patients more quickly.

In January 2021, we announced the dosing of the first patient in our Phase 2b study in patients with severe AH (AHFIRM). AHFIRM is a randomized, double-blind, placebo-controlled, international, multi-center Phase 2b study to evaluate the safety and efficacy of larsucosterol in approximately 300 patients with severe AH. The study is comprised of three arms targeting approximately 100 patients each: (1) Placebo plus supportive care, with or without methylprednisolone capsules at the investigators' discretion; (2) larsucosterol (30 mg); and (3) larsucosterol (90 mg). Patients in the larsucosterol arms receive the same supportive care without steroids. In order to maintain blinding, patients in the two active arms receive matching placebo capsules if the investigator prescribes steroids. Patients receive an intravenous (IV) dose of larsucosterol or placebo (sterile water) on Day 1 and a second identical IV dose on Day 4 if they are still hospitalized. The primary outcome measure will be the 90-Day incidence of mortality or liver transplantation for patients treated with larsucosterol compared to those treated with placebo. Secondary endpoints include the difference in 90-Day mortality between patients treated with larsucosterol compared to those treated with placebo, the difference in 28-Day mortality or liver transplantation for patients treated with larsucosterol compared to those treated with placebo, and the difference in mortality between patients treated with larsucosterol compared to those treated with placebo. We now have over 60 clinical trial sites across the United States, U.K., E.U. and Australia.

Phase 1 trials of larsucosterol administered through injection have supported the development of larsucosterol in AH. The initial Phase 1 trial in healthy subjects was a single-site, randomized, double-blinded, placebo-controlled, single-ascending-dose study that evaluated the safety, tolerability and PK of intramuscular (IM) injected larsucosterol. The 24-subject study (16 healthy volunteers on larsucosterol and 8 on placebo) of four escalating dose levels resulted in dose proportional systemic exposure of larsucosterol. Larsucosterol was well-tolerated at all dose levels, with no serious treatment-related adverse events reported. We also conducted a multiple-dose study involving 10 healthy subjects, in which participants received IM-injected larsucosterol for five consecutive days (8 subjects on larsucosterol, 2 on placebo) using the next to highest dose from the single dose study. No serious treatment related adverse events were reported, no subjects withdrew from the study, no accumulation in plasma concentrations were observed with repeat dosing, and the pain scores and injection site reactions were minimal. We also conducted a single-ascending dose intravenous (IV) infusion study with 16 healthy subjects and observed no treatment-related serious adverse events. The systemic exposure following IV infusion was dose proportional.

A Phase 1 drug-drug interaction study conducted in healthy subjects demonstrated that neither orally administered nor intravenously injected larsucosterol at doses tested affected the safety and PK of midazolam, a drug metabolized by CYP3A4, which is one of the important enzymes associated with clinically relevant drug-drug interactions.

We have also conducted a Phase 1b study with injected larsucosterol in patients with impaired kidney function (stage 3 and 4 chronic kidney disease (CKD)) and matched control subjects (MCS), matched by age, body mass and gender with normal kidney function. This study was a single-site, open-label, single-ascending-dose study in two successive cohorts (first a low dose of 30 mg and then a high dose of 120 mg) evaluating safety and PK of intramuscular injected larsucosterol. The low dose cohort consisted of 6 patients with CKD and 3 MCS; the high dose cohort consisted of 5 CKD patients and 3 MCS. In this trial, larsucosterol was well tolerated among all subjects and the PK parameters between the kidney function impaired patients and the MCS were comparable.

Chronic Liver Disease Program with Orally Administered Larsucosterol

Market Opportunity. Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in both children and adults. It is estimated that NAFLD affects approximately 30% to 40% of adults and 10% of children in the United States. Non-alcoholic steatohepatitis (NASH), a more severe and progressive form of NAFLD, is one of the most common chronic liver diseases worldwide, with an estimated prevalence of 3-5% globally. No drug is currently approved for treatment of NAFLD or NASH. In addition to these liver diseases, there are a number of orphan liver diseases for which we may seek to develop larsucosterol.

Clinical Program. In 2020, we completed a Phase 1b randomized, multi-center, and open-label clinical study in the United States to evaluate safety, PK and signals of biological activity of larsucosterol in NASH patients with stage 1-3 fibrosis. Larsucosterol (at doses of 50 mg QD, 150 mg QD and 300 mg BID) was administered orally for 28 days with 20 patients or more per dose group for a total of 65 patients in the trial. Key endpoints included safety and PK, and clinical chemistry/efficacy signals, such as liver enzymes


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(ALT, AST and GGT), serum lipids (e.g., triglycerides), biomarkers (e.g., CK-18s, inflammatory cytokines), and insulin resistance (i.e., HOMA-IR), as well as liver fat content and liver stiffness by imaging (e.g., MRI-PDFF (as defined below) and FibroScan®).

Both the 50 mg and 600 mg dose groups showed a statistically significant median reduction at Day 28 from baseline of serum alanine aminotransferase ("ALT") levels at -16% and -17%, respectively. The 600 mg dose group also showed statistically significant median reductions at Day 28 from baseline of serum aspartate aminotransferase ("AST") (-18%) and gamma-glutamyl transferase ("GGT") (-8%), and the 50 mg dose group had a statistically significant reduction at Day 28 from baseline in liver stiffness as measured by Fibroscan (-10%).

Patients in the 50 mg or 150 mg dose groups also had statistically significant median reduction at Day 28 from baseline of serum triglycerides (-13% in the 50 mg group) or LDL-C (-11% in the 150 mg group). Patients with elevated baseline triglycerides (?200 mg/dL; n=16) across all dose groups had a median reduction at Day 28 from baseline of -24% (p <0.01). Furthermore, patients in the 50 mg and 150 mg groups had 22% and 18% median reductions (not statistically significant) of HOMA-IR from baseline respectively after 4 weeks of daily oral dosing of larsucosterol. The 600 mg group did not show a change in HOMA-IR.

At Day 28, 43% of patients in all three dose groups showed ? 10% liver fat reduction from baseline as measured by magnetic resonance imaging - proton density fat fraction (MRI-PDFF). In this subgroup, there was a significant reduction from baseline in median liver fat content (-18%, -19%, and -23%, in the 50 mg, 150 mg and 600 mg groups respectively). The reduction of liver fat content was accompanied by a significant median reduction from baseline of serum ALT (-21%, -19%, and -32%, in the 50 mg, 150 mg and 600 mg groups respectively), as well as both CK-18, M30 and M65 in the 50 mg and 600 mg groups.

Larsucosterol was well tolerated at all three doses evaluated. There were no serious adverse events reported during the study, and no discontinuations, early withdrawals or termination of study drug or study participation due to adverse events. PK parameters after repeat dosing were comparable to those after a single dose (from a prior study), indicating no accumulation of the drug after repeat dosing. We are working with a number of disease experts to determine next steps for larsucosterol in NASH.

We have completed multiple Phase 1 trials in healthy subjects with orally administered larsucosterol. These include single-ascending-dose and multiple-ascending-dose studies as well as a food effect study. In all of these studies larsucosterol was well-tolerated at all dose levels, with no serious treatment-related adverse events reported. Dose-related increases in plasma concentrations were observed and no accumulation in plasma concentrations or food effects were observed with repeat dosing.

We also conducted a Phase 1b trial in cirrhotic and non-cirrhotic NASH patients and matched control subjects ("MCS") (matched by age, body mass index and gender with normal liver function) utilizing orally administered larsucosterol. This was an open-label, single-ascending-dose safety and PK study conducted in Australia in two successive dose cohorts (first a low dose of 50 mg and then a high dose of 200 mg). Both cohorts consisted of 10 NASH patients and 6 MCS. Data from this study was presented at the International Liver Congress™ 2017 organized by the European Association for the Study of the Liver (EASL) in Amsterdam in April 2017. All patients and MCS in this study tolerated larsucosterol well. One patient (with a prior history of arrhythmia and an ongoing viral infection) in the high dose cohort experienced a serious adverse event (i.e., shortness of breath), which occurred without unusual biochemical changes and resolved without intervention but was considered possibly treatment related by the physician due to its temporal association with dosing. In both low and high dose cohorts, the PK parameters were comparable between the NASH patients and the MCS. In addition, the systemic exposure following the low and high doses of larsucosterol was dose dependent.

While this study was not designed to assess efficacy, we observed statistically significant reductions from baseline levels of several biomarkers after both doses of larsucosterol. A single oral dose of larsucosterol significantly reduced the levels of both full-length (M65) and cleaved (M30) cytokeratin-18 (CK-18), bilirubin, hsCRP, and IL-18 in these subjects. The mean reduction of full-length CK-18 (a generalized cell death marker) at the measured time point of greatest effect (12 hours after dosing) was 33% in the low dose cohort and 41% in the high dose cohort. The mean decrease of cleaved CK-18 (a cell apoptosis marker) at the measured time point of greatest effect (12 hours after dosing) was 37% in the low dose cohort and 47% in the high dose cohort. The mean reduction of total bilirubin (a liver function marker) at the measured time point of greatest effect (12 hours after dosing) was 27% in the low dose cohort and 31% in the high dose cohort. The mean decrease of high sensitivity C-Reactive Protein (hsCRP) (a marker of inflammation) at the measured time point of greatest effect (24 hours after dosing) was 8% in the low dose cohort and 13% in the high dose cohort. The mean decrease of IL-18 (an inflammatory mediator) at the measured time point of greatest effect (8 hours after dosing) was 4% in the low dose cohort and 8% in the high dose cohort.

We have also conducted a Phase 1b open-label, multi-center U.S. study to evaluate the safety, tolerability, and pharmacokinetics (PK) of larsucosterol in subjects with moderate (Child-Pugh B scores, n=10) and severe (Child-Pugh C scores, n=7) hepatic function impairment (HI), and MCS (n=10) with normal hepatic function. Each subject received a single oral dose of 200 mg larsucosterol. Results from this study were presented at the International Liver Conference 2021 (EASL). Larsucosterol was safe and well-tolerated by all moderate and severe HI subjects with no adverse events and no dose-limiting toxicity reported throughout the study. As expected, clearance of larsucosterol was decreased in HI subjects compared to MCS with normal hepatic function, resulting in a 4-10-fold higher drug exposure (Cmax and AUC) in HI subjects. Additionally, a single oral dose of 200 mg of larsucosterol in subjects with HI resulted in statistically significant median reductions from baseline of the apoptosis biomarker M30 (cCK-18) at 12 hours post-dose.


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Collectively, the biological signals observed in NASH and HI patients plus results from our animal models and cell culture studies suggest potential therapeutic activity of larsucosterol for patients with liver diseases. However, additional studies are required to evaluate the safety and efficacy of larsucosterol, and there is no assurance that these biomarker, clinical chemistry and liver imaging effects will be associated with clinically relevant benefits, or that larsucosterol will demonstrate safety or efficacy in treating liver diseases in our ongoing or future trials.

Approved and Commercial Pharmaceutical Products


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POSIMIR® (bupivacaine solution)

POSIMIR (bupivacaine solution) for infiltration use is a novel and proprietary product that combines the strength of 660 mg of bupivacaine base with the innovative SABER® platform technology, enabling continuous sustained delivery of a non-opioid local analgesic over three days in adults, which we believe coincides with the time period of the greatest need for post-surgical pain control in most patients. POSIMIR contains more bupivacaine than any other approved single-dose sustained-release bupivacaine product. At the end of surgery, POSIMIR is administered into the subacromial space under direct arthroscopic visualization, where it continuously releases bupivacaine for 72 hours or more.

In February 2021, the FDA approved POSIMIR for infiltration use in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.

In December 2021, we entered into a license agreement (the "Innocoll Agreement") with Innocoll. Pursuant to the Innocoll Agreement, we granted to Innocoll an exclusive, royalty-bearing, sublicensable right and license to develop, manufacture and commercialize POSIMIR in the United States. The Innocoll Agreement provides for the assignment of our supply agreement with a contract manufacturing organization to Innocoll and also provides Innocoll with the right, within the United States, to expand the approved indications of POSIMIR. We retain, outside the United States, all of the global rights to POSIMIR. Innocoll paid us an initial non-refundable, upfront fee of $4.0 million as well as a fee in the amount of $1.3 million primarily to cover the manufacturing supplies and excipients and certain equipment transferred to Innocoll pursuant to the terms of the Innocoll Agreement, and certain recently incurred DURECT expenses the parties negotiated for Innocoll to reimburse. In the fourth quarter of 2021, we recognized $4.1 million as collaborative research and development and other revenue, $1.1 million as product revenue, and a reduction of $0.1 million in net equipment. At December 31, 2021, we included $5.3 million due from Innocoll in accounts receivable on our balance sheet; these funds were received in January 2022. On August 2, 2022, we were issued a new patent by the US Patent Office, extending US patent coverage for POSIMIR to at least 2041. Under our agreement with Innocoll, this triggers an $8.0 million milestone payment due to us. We will also receive $2.0 million upon the first commercial sale of POSIMIR in the United States. We are eligible to receive additional milestone payments of up to $130.0 million in the aggregate (including the $8.0 million patent milestone payment), depending on the achievement of certain regulatory, commercial, and intellectual property milestones with respect to POSIMIR. In addition, upon commercialization, we will receive tiered low to mid-double-digit royalty payments of net sales of


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POSIMIR in the United States. Pursuant to the terms of the Innocoll Agreement, except as otherwise expressly provided in the Innocoll Agreement, Innocoll is responsible for expenses relating to the manufacturing, development and commercialization of POSIMIR in the United States. We believe Innocoll is currently in the final stages of commercial launch preparation.

PERSERIS™(risperidone)

In September 2017, we entered into an agreement with Indivior, under which we assigned to Indivior certain patents that may provide further intellectual property protection for PERSERIS, Indivior's extended-release injectable suspension for the treatment of schizophrenia in adults. In consideration for such assignment, Indivior made non-refundable upfront and milestone payments to DURECT totaling $17.5 million. Additionally, under the terms of the agreement with Indivior, DURECT receives quarterly earn-out payments that are based on a single digit percentage of U.S. net sales of PERSERIS into 2026. Indivior commercially launched PERSERIS in the U.S. in February 2019.

ORADUR™-ADHD Program

We developed a proprietary drug product for the treatment of ADHD called Methydur in collaboration with Orient Pharma, a diversified multinational pharmaceutical, healthcare and consumer products company with headquarters in Taiwan. We have licensed worldwide Methydur rights to OP and they launched Methydur commercially in Taiwan in September 2020. OP may seek commercialization partners in other countries throughout the world, including China and the U.S. We receive a single digit royalty on sales of Methydur by OP or its commercialization partners as well as potential milestones and sub-license fees.

Drug Delivery Technologies and Programs

Our drug delivery technologies are designed to deliver the right drug to the right place, in the right amount and at the right time to treat a variety of chronic, acute and episodic diseases and conditions. We aim to improve therapy for a given disease or patient population by controlling the rate and duration of drug administration. In addition, if advantageous for the therapy, our technologies can target the delivery of the drug to its intended site of action.

Our technologies are suitable for providing long-term drug therapy because they can often store highly concentrated, stabilized drugs in a small volume and protect the drug from degradation by the body. This, in combination with the ability to continuously deliver desired doses of a drug, can extend the therapeutic value of a wide variety of drugs, including, in some cases, those which would otherwise be ineffective, too unstable, too potent or cause adverse side effects. In some cases, delivering the drug directly to the intended site of action can improve efficacy while minimizing unwanted side effects elsewhere in the body, which may limit the long-term use of many drugs. Our technologies may thus provide better therapy for chronic diseases or conditions, or for certain acute conditions where longer drug dosing is required or advantageous, by replacing multiple injection therapy or oral dosing, improving drug efficacy, reducing side effects and ensuring dosing compliance. Our technology may thereby improve patients' quality of life by eliminating more repetitive treatments, reducing dependence on caregivers and allowing patients to lead more independent lives.

We currently focus our drug delivery technology efforts around our SABER and CLOUD Bioerodible Injectable Depot Systems. SABER uses a high viscosity base component, such as sucrose acetate isobutyrate (SAIB), to provide controlled release of a drug. When the high viscosity SAIB is formulated with drug, biocompatible excipients and other additives, the resulting formulation is easily injectable with standard syringes and needles. After injection of a SABER formulation, the excipients diffuse away over time, leaving a viscous depot which provides controlled sustained release of drug. CLOUD is a class of bioerodible injectable depot technology which generally does not contain SAIB but includes various other release rate modifying excipients and/or bioerodible polymers to achieve the delivery of drugs for periods of days to months from a single injection.

The SABER technology is the basis of POSIMIR (described above). The SABER technology is also utilized in our ophthalmic program with Santen Pharmaceutical Co., Ltd. (Santen), as well as in feasibility programs.

Product Revenues

We also currently generate product revenue from the sale of two product lines:

  • ALZET® osmotic pumps which are used for animal research; and


   •  certain key excipients that are included in Methydur and one excipient that
      is included in POSIMIR and in a marketed animal health product.

Because we consider our core business to be developing and commercializing pharmaceuticals, we do not intend to significantly increase our investments in or efforts to sell or market any of our existing product lines. However, we expect that we will continue to make efforts to increase our revenues related to collaborative research and development by extending and expanding our current collaborations as well as entering into additional research and development agreements with third-party collaborators to develop product candidates based on our drug delivery technologies.

Operating Results

Since our inception in 1998, we have generally had a history of operating losses. At June 30, 2022, we had an accumulated deficit of $548.4 million. Our net losses were $11.5 million and $22.4 million for the three and six months ended June 30, 2022


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compared with net losses of $9.1 million and $19.3 million for the corresponding periods in 2021. These losses have resulted primarily from costs incurred to research and develop our product candidates and to a lesser extent, from selling, general and administrative costs associated with our operations and product sales. We expect our research and development expenses in the near future to increase compared to the second quarter of 2022 as we continue to incur research and development expenses related to larsucosterol. We expect our selling, general and administrative expenses in the near future to be comparable to the second quarter of 2022. Over the next twelve months, we anticipate a limited increase in revenues primarily from the launch of POSIMIR by our licensee, Innocoll. However, we expect to incur continuing losses and negative cash flows from operations for the foreseeable future.

Critical Accounting Policies and Estimates

The preparation of financial statements in conformity with U.S. generally accepted accounting principles requires management to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the dates of the financial statements and the reported amounts of revenues and expenses during the reporting periods. The most significant estimates and assumptions relate to revenue recognition, prepaid and accrued contract research expenses, and stock-based compensation. Actual amounts could differ significantly from these estimates. There have been no material changes to our other critical accounting policies and estimates as compared to the disclosures in our annual report on Form 10-K for the year ended December 31, 2021.

Results of Operation

Three and six months ended June 30, 2022 and 2021

Collaborative research and development and other revenue

We recognize revenues from collaborative research and development activities and service contracts. Collaborative research and development and other revenue primarily represents reimbursement of qualified expenses related to collaborative agreements with various third parties to research, develop and commercialize potential products using our drug delivery technologies, and revenue from the recognition of upfront fees and milestone payments in connection with our collaborative or license agreements.

We expect our collaborative research and development and other revenues to fluctuate in future periods pending our efforts to enter into potential new collaborations, our existing third-party collaborators' commitment to and progress in the research and development programs, and any royalty or earn-out revenue recognized from collaborators or counterparties. The collaborative research and development and other revenues associated with our major collaborators or counterparties are as follows (in thousands):



                                               Three months ended              Six months ended
                                                    June 30,                       June 30,
                                              2022             2021           2022          2021
Total collaborative research and
development and other
  revenue (1)                              $      606       $      735     $    1,101     $   1,309


(1) Includes: (a) amounts related to earn-out revenue from Indivior UK Limited

    (Indivior) with respect to PERSERIS net sales; (b) feasibility programs; (c)
    research and development activities funded by Santen Pharmaceutical Co. Ltd.
    (Santen) and (d) royalty revenue from Orient Pharma with respect to Methydur
    net sales. Since 2018, we from time to time have been working with Santen on
    a limited set of research and development activities funded by Santen.

Product revenue

A portion of our revenues is derived from product sales, which include our ALZET mini pump product line, and certain excipients that are included in Methydur and in an animal health product. Net product revenues were $1.5 million and $2.9 million for the three and six months ended June 30, 2022 compared with $1.6 million and $3.2 million for the corresponding periods in 2021. The decreases in the three and six months ended June 30, 2022 were primarily attributable to lower revenue from our ALZET mini pump product line as a result of lower units sold, partially offset by higher revenue from certain excipients that are included in Methydur and in an animal health product compared to the corresponding periods in 2021.

Cost of product revenues

Cost of product revenues were $393,000 and $728,000 for the three and six months ended June 30, 2022 compared with $359,000 and $711,000 for the corresponding periods in 2021. Cost of product revenues in the three and six months ended June 30, 2022 increased slightly primarily due to higher costs of goods associated with certain excipients that are included in Methydur and in an animal health product, partially offset by lower units sold from our ALZET product line compared to the corresponding periods in 2021. Stock-based compensation expense recognized related to cost of product revenues was $5,000 and $10,000 for the three and six months ended June 30, 2022 compared to $6,000 and $11,000 for the corresponding periods in 2021.

We had 10 manufacturing employees in each of the six months ended June 30, 2022 and 2021. We expect the number of employees involved in manufacturing will remain comparable in the near future.


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Research and development

Research and development expenses are primarily comprised of salaries, benefits, stock-based compensation and other compensation cost associated with research and development personnel, overhead and facility costs, preclinical and non-clinical development costs, clinical trial and related clinical manufacturing costs, contract services, and other outside costs.

Research and development expenses were $8.8 million and $17.0 million for the three and six months ended June 30, 2022 compared to $7.4 million and $15.4 million for the corresponding periods in 2021. We incurred higher research and development costs associated with larsucosterol, partially offset by lower research and development costs associated with POSIMIR, the depot injectable programs, a now-terminated Gilead program and other research programs in the three months ended June 30, 2022 compared to the corresponding period in 2021, as more fully discussed below. We incurred higher research and development costs associated with larsucosterol and the depot injectable programs, partially offset by lower research and development costs associated with POSIMIR, the Gilead program and other research programs in the six months ended June 30, 2022 compared to the corresponding periods in 2021, as more fully discussed below. Stock-based compensation expense recognized related to research and development personnel was $296,000 and $626,000 for the three and six months ended June 30, 2022 compared to $320,000 and $635,000 for the corresponding periods in 2021. As of June 30, 2022, we had 43 research and development employees compared with 45 as of June 30, 2021. We expect research and development expenses in the near future to increase compared to the second quarter of 2022 as we expect to incur higher research and development expenses for larsucosterol.

                                            Three months ended          Six months ended
                                                 June 30,                   June 30,
                                             2022          2021         2022         2021
Larsucosterol                             $    8,104      $ 5,955     $ 15,362     $ 11,471
Depot injectable programs                        376          441          806          703
POSIMIR                                          154          785          490        2,459
Gilead                                             -            -            -           65
Others                                           183          252          370          710

Total research and development expenses $ 8,817 $ 7,433 $ 17,028 $ 15,408

Larsucosterol

Our research and development expenses for larsucosterol were $8.1 million and $15.4 million in the three and six months ended June 30, 2022 compared to $6.0 million and $11.5 million for the corresponding periods in 2021. The increases in the three and six months ended June 30, 2022 were primarily due to higher clinical trial related expenses and higher employee-related costs for larsucosterol, partially offset by lower contract manufacturing expenses for this drug candidate compared with the corresponding periods in 2021.

We continue to assess the impact of the COVID-19 outbreak on our business, including our larsucosterol Phase 2b trial in alcohol-associated hepatitis; COVID-19 may affect our ability to initiate and/or complete recruitment and data analysis for our clinical trials, including larsucosterol trials, in our planned timeframe.

Depot injectable programs

Our research and development expenses for depot injectable programs were $376,000 and $806,000 in the three and six months ended June 30, 2022 compared to $441,000 and $703,000 for the corresponding periods in 2021. The decrease in the three months ended June 30, 2022 was primarily due to lower outside expenses for these programs compared with the corresponding period in 2021. The increase in the six months ended June 30, 2022 was primarily due to higher employee-related costs for these programs compared with the corresponding period in 2021.

POSIMIR

Our research and development expenses for POSIMIR were $154,000 and $490,000 in the three and six months ended June 30, 2022 compared to $785,000 and $2.5 million for the corresponding periods in 2021. The decreases in the three months ended June 30, 2022 was primarily due to lower manufacturing supplies and lower employee related costs for this program compared with the corresponding period in 2021. The decrease in the six months ended June 30, 2022 was primarily due to lower consulting expenses and employee related costs for this program compared with the corresponding periods in 2021.

It is possible that COVID-19 will adversely impact the timing of potential commercialization of POSIMIR which is now controlled by Innocoll.

Gilead Program

Our research and development expenses for the Gilead program were zero in each of the three and six months ended June 30, 2022 compared to zero and $65,000 for the corresponding periods in 2021. The decrease in the six months ended June 30, 2022 was primarily due to lower employee-related costs devoted to the program compared with the corresponding period in 2021. In June 2020, Gilead provided notice that it was terminating our agreements with them.


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Other DURECT research programs

Our research and development expenses for all other programs were $183,000 and $370,000 in the three and six months ended June 30, 2022 compared to $252,000 and $710,000 for the corresponding periods in 2021. The decreases in the three and six months ended June 30, 2022 was primarily due to lower employee-related costs associated with these programs compared with the corresponding periods in 2021.

We cannot reasonably estimate the timing and costs of our research and development programs due to the risks and uncertainties associated with developing pharmaceuticals as outlined in the "Risk Factors" section of this report. The duration of development of our research and development programs may span as many as ten years or more, and estimation of completion dates or costs to complete are highly speculative and subjective due to the numerous risks and uncertainties associated with developing pharmaceutical products, including significant and changing government regulation, the uncertainties of future preclinical and clinical study results, uncertainties related to COVID-19, the uncertainties with our collaborators' commitment to and progress in the programs and the uncertainties associated with process development and manufacturing as well as sales and marketing. In addition, with respect to our development programs subject to third-party collaborations, the timing and expenditures to complete the programs are subject to the control of our collaborators. Therefore, we cannot reasonably estimate the timing and costs of the efforts necessary to complete the research and development programs. For additional information regarding these risks and uncertainties, see "Risk Factors" below.

Selling, general and administrative. Selling, general and administrative expenses are primarily comprised of salaries, benefits, stock-based compensation and other compensation costs associated with finance, legal, business development, sales and marketing and other administrative personnel, overhead and facility costs, and other general and administrative costs.

Selling, general and administrative expenses were $4.0 million and $7.7 million in the three and six months ended June 30, 2022 compared to $3.2 million and $6.7 million for the corresponding periods in 2021. The increases in the three and six months ended June 30, 2022 were primarily due to higher patent expenses as well as higher consulting and employee expenses compared to the corresponding periods in 2021. Stock-based compensation expense recognized related to selling, general and administrative personnel was $317,000 and $660,000 for the three and six months ended June 30, 2022 compared to $384,000 and $766,000 for the corresponding periods in 2021.

We had 25 selling, general and administrative employees as of June 30, 2022 compared with 24 as of June 30, 2021. We expect selling, general and administrative expenses in the near future to be comparable to the second quarter of 2022.

Other income (expense). Interest and other income was $127,000 and $181,000 for the three and six months ended June 30, 2022 compared to $39,000 and $76,000 for the corresponding periods in 2021. The increases in the three and six months ended June 30, 2022 were primarily due to higher interest rates associated with our cash and investments compared with the corresponding periods in 2021.

Interest and other expense was $592,000 and $1.1 million for the three and six months ended June 30, 2022 compared to $528,000 and $1.1 million for the corresponding periods in 2021. The increases in the three and six months ended June 30, 2022 were primarily due to higher interest rates on our term loan compared with the corresponding periods in 2021.

Liquidity and Capital Resources

We had cash, cash equivalents and investments totaling $54.3 million at June 30, 2022 compared to cash, cash equivalents, cash held in escrow and investments of $70.0 million at December 31, 2021. These balances include $150,000 of interest-bearing marketable securities classified as restricted investments on our balance sheets as of June 30, 2022 and December 31, 2021. The decrease in cash, cash equivalents and investments was primarily due to cash used in ongoing operating activities and interest payments, partially offset by payments received from collaboration partners and customers. At December 31, 2021, we included $5.3 million due from Innocoll in accounts receivable on our balance sheet; these funds were received in January 2022.

We used $15.6 million of cash in operating activities for the six months ended June 30, 2022 compared to $18.8 million for the corresponding period in 2021. The cash used for operations was primarily to fund operations as well as our working capital requirements, partially offset by the changes in accounts receivable, prepaid expenses and other assets, and accrued and other liabilities.

We generated $12.9 million of cash in investing activities for the six months ended June 30, 2022 compared to $3.1 million for the corresponding period in 2021. The increase in cash provided by investing activities was primarily due to a decrease in net purchases of available-for-sale securities partially offset by a decrease in proceeds from maturities of available-sale-securities for the six months ended June 30, 2022 compared with the corresponding period in 2021. In addition, we received $15 million of cash from sale of the LACTEL product line in the six months ended June 30, 2021.

We received $34,000 of cash from financing activities for the six months ended June 30, 2022 compared to $50.5 million for the corresponding period in 2021. The decrease in cash received from financing activities was primarily due to our election not to sell shares under our shelf registration statement as well as lower proceeds from the exercise of stock options in the six months ended June 30, 2022 compared with the corresponding period in 2021. In February 2021, we completed an underwritten public offering of 20,364,582 shares of our common stock at a price of $2.2386 per share pursuant to an underwriting agreement with Cantor Fitzgerald & Co., raising total gross proceeds of approximately $45.6 million before deducting estimated offering expenses. Total


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stock issuance costs related to this financing were approximately $195,000, resulting in net proceeds of approximately $45.4 million. In the six months ended June 30, 2021, we also raised net proceeds (net of commissions) of approximately $2.4 million from the sale of 950,009 shares of our common stock in the open market at a weighted average price of $2.60 per share pursuant to the October 2018 registration statement and 2015 Sales Agreement.

We anticipate that cash used in operating activities in the near future will increase compared to the second quarter of 2022 as we experience higher research and development expenses related to larsucosterol.

In July 2021, we filed a shelf registration statement on Form S-3 with the SEC (the "2021 Registration Statement") (File No. 333-258333), which upon being declared effective in August 2021, terminated our registration statement filed in August 2018 (File No. 333-226518) and allowed us to offer up to $250.0 million of securities from time to time in one or more public offerings, inclusive of up to $75.0 million of shares of our common stock which we may sell, subject to certain limitations, pursuant to a sales agreement dated July 30, 2021 with Cantor Fitzgerald (the "2021 Sales Agreement"). The 2021 Sales Agreement replaced a prior 2015 Sales Agreement.

As of August 3, 2022, we had up to $250.0 million of our securities available for sale under the 2021 Registration Statement, of which $75.0 million of our common stock are available pursuant to the 2021 Sales Agreement.

Any material sales in the public market of our common stock, under the 2021 Sales Agreement or otherwise under the 2021 Registration Statement, could adversely affect prevailing market prices for our common stock.

During the six months ended June 30, 2022, there were no significant changes in our commercial commitments and contractual obligations as compared with the information presented in our Annual Report on Form 10-K for the year ended December 31, 2021.

The COVID-19 pandemic is continuing to impact our business in several ways. COVID-19 has had a negative impact on orders for our ALZET product line as many ALZET customers reduced their activities during the pandemic. For larsucosterol, we may continue to experience delays in patient enrollment in the Phase 2b AHFIRM clinical trial or disruptions in supplies of larsucosterol or other items required for clinical trials. Delays and potential disruptions would increase the overall costs of development of larsucosterol. We are actively monitoring the impact of COVID-19 and the possible effects on our financial condition, liquidity, operations, clinical trials, suppliers, industry and workforce. However, the full extent, consequences, and duration of COVID-19 and the resulting impact on the Company cannot currently be predicted. We will continue to evaluate the impact that these events could have on our operations, financial position, and the results of operations and cash flows. Additional volatility in capital markets and/or clinical trial delays resulting from the impacts of COVID-19 may also limit our ability to raise capital on acceptable terms, if at all.

We believe that our existing cash, cash equivalents and investments will be sufficient to fund our planned operations, existing debt and contractual commitments and planned capital expenditures through at least the next 12 months from June 30, 2022. We may consume available resources more rapidly than currently anticipated, resulting in the need for additional funding. Over the next twelve months, we anticipate a limited increase in revenues primarily from the launch of POSIMIR by Innocoll. However, we expect to incur continuing losses and negative cash flows from operations for the foreseeable future.

Depending on whether we enter into additional collaborative agreements in the near term and the extent to which we earn revenues from our collaborative agreements, we may decide to raise additional capital through a variety of sources in the short-term and in the long-term, including:

  • the public equity markets;


  • private equity financings;


  • collaborative arrangements; and/or


  • public or private debt.

There can be no assurance that we will enter into additional collaborative agreements or maintain existing collaborative agreements in the near term, will earn collaborative revenues or that additional capital will be available on favorable terms, if at all. If adequate funds are not available, we may be required to significantly reduce or refocus our operations or to obtain funds through arrangements that may require us to relinquish rights to certain of our products, technologies or potential markets, either of which could have a material adverse effect on our business, financial condition and results of operations. To the extent that additional capital is raised through the sale of equity or convertible debt securities, the issuance of such securities would result in ownership dilution to our existing stockholders (assuming convertible debt securities were converted into shares).

Our cash and investments policy emphasizes liquidity and preservation of principal over other portfolio considerations. We select investments that maximize interest income to the extent possible given these two constraints. We satisfy liquidity requirements by investing excess cash in securities with different maturities to match projected cash needs and limit concentration of credit risk by diversifying our investments among a variety of high credit-quality issuers.


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We are experiencing certain operational and other challenges as a result of COVID-19, which could delay or halt our research and development programs or clinical programs. See Item 1A - Risk Factors for further discussion of the current and expected impact on our business and programs.

Available information

Our corporate website address is www.durect.com. We use the investor relations page of our website for purposes of compliance with Regulation FD and as a routine channel for distribution of important information, including news releases, analyst presentations, financial information and corporate governance practices. Our filings with the SEC are posted on our website and available free of charge as soon as reasonably practical after they are electronically filed with, or furnished to, the SEC. The SEC's website, www.sec.gov, contains reports, proxy statements and other information regarding issuers that file electronically with the SEC. The content on any website referred to in this Quarterly Report on Form 10-Q is not incorporated by reference in this Form 10-Q unless expressly noted. Further, the Company's references to website URLs are intended to be inactive textual references only.

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