GTC Bio Diabetes Summit

April 23-25, 2014; Cambridge, MA Day #2 Highlights - Draft

Executive Highlights

Consistent with last year’s meeting, the GTC Bio 2014 Diabetes Summit brought a number of big names in diabetes together in a small room. The Summit connects leaders in academia, biotech, and big pharma to discuss the future of diabetes research and care on the scenic banks of the Charles River in Cambridge. Attesting to the meeting’s success in this regard, NeoStem CEO Dr. Douglas Losordo even commented that after seeing data for an early stage oncology candidate at a past GTC Bio meeting, he led NeoStem to acquire the promising agent.

The second day of the meeting was the most heavily scheduled day of the meeting, and as expected, it yielded some valuable updates and other learning. High-profile cardiologist Dr. Steve Nissen delivered a talk on the need for better diabetes drugs and better regulatory processes for those drugs, and did not mince his words, characterizing the FDA EMDAC as  “functionally brain-dead” for focusing on drugs’ glucose lowering rather than their impact on outcomes. On a slightly more positive note, we learned from Novo Nordisk Director of Strategy and Innovation Sourcing Dr. Tomas Landh that the company is looking to develop new therapies for some of the microvascular and cardiovascular complications of diabetes (including retinopathy and neuropathy). The day also featured presentations on Mercodia’s ultra-sensitive C-peptide ELISA assay, Intarcia’s implantable exenatide mini-pump ITCA-650, Oramed’s oral insulin ORMD-0801, and Dr. Denise Faustman’s (Harvard Medical School, Boston, MA) controversial “vaccine” to reverse type 1 diabetes.

Many speakers underscored the increasing criticality of inter-sector partnerships. In a panel discussion on industry-academia partnerships, Ms. Lita Nelsen (Director, Technology Licensing Office, MIT, Cambridge, MA) explained that industry, before pursuing partnerships in academic, must accept that academic institutions are limited by a number of non-negotiable rules (the need to publish, financial and legal restrictions, etc.). Mr. John Brooks (President and CEO, Joslin Diabetes Center, Boston, MA) raised Joslin as an example of an academic body working with industry, and noted that Joslin’s new program to assist with trial design and execution already has industry participants. We also saw an example of a big pharma-academia-biotech triple partnership at the meeting. Biotech NeoStem is working with both Becton-Dickinson and UC San Francisco (specifically Drs. Jeffrey Bluestone and Steven Gitelman) on a phase-2-ready immunomodulator for type 1 diabetes.

Included below are our top ten highlights from the day, along with an honorable mention for good measure. Stay tuned for our coverage of the third and final day of the meeting!

Top Ten Highlights

1. The famous (infamous?) cardiologist Dr. Steve Nissen (Cleveland Clinic, Cleveland, OH) gave a strongly-worded talk on the need for better glucose-lowering drugs. The format and central theme of his presentation were preserved from higher-profile talks he gave at last year’s EASD and IDF – however, perhaps given the more intimate setting of GTC Bio, he did not mince his words when discussing his harsh negative opinions on the diabetes drug development and regulatory processes over the past few decades. He stated that the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) is the weakest division of the FDA, and is “functionally braindead” for ignoring poor diabetes drug outcomes data from early trials (the UGDP, for example) and allowing approval to be based solely on short-term glucose-lowering. Dr. Nissen downplayed the finding from the UKPDS metformin subgroup analysis (a subgroup of a subgroup) of a reduction in myocardial infarction and stroke with metformin. He also criticized the broader medical community for flocking to agents that have no safety data, suggesting that DPP-4 inhibitors are perceived as safe simply because they have not been studied enough (he called the class “pathetically weak” at lowering blood sugar). Although there were some quotes worth heeding in Dr. Nissen’s presentation (“There is no virtue in practicing medicine in an evidence-free zone”), the tone of much of his presentation was highly confrontational.  

2. Dr. Tomas Landh, Director of Strategy and Innovation Sourcing in Diabetes at Novo Nordisk, provided an exciting look into the research and disease areas the company is entering. We were very excited to hear that the company is now pursuing therapies for the late-stage complications of diabetes, focusing on nephropathy and retinopathy. Additionally, the company is considering moving into therapy development for the macrovascular complications of diabetes. Given the company’s expertise in biologics development, its deep experience in the diabetes field, and the enormous unmet need for therapies for diabetes complications such as chronic kidney disease, we see this as both a very welcome and a very logical move for Novo Nordisk. Dr. Landh also emphasized Novo Nordisk’s work in oral biologics, such as oral insulin and GLP-1 agonists (see our Novo Nordisk 4Q13 Report for more on that front).

3. Dr. Hans-Juergen Woerle (VP and Head of Therapeutic Area Metabolism, Boehringer Ingelheim) raised attention to the growing size of clinical development programs for type 2 diabetes candidates even excluding CVOTs. Metformin was approved in 1999 based on a clinical program that enrolled ~1,500 people. In contrast, the three candidates approved in 2013 (Takeda’s Nesina [alogliptin], J&J’s Invokana [canagliflozin], and AZ’s Farxiga [dapagliflozin]) all had pre-marketing programs of about 10,000 people, and Lilly/BI’s development program for Jardiance (empagliflozin) enrolled over 13,000 people. Reasons for the rising development costs, identified by Dr. Woerle, included the need for more head-to-head comparison trials in order for companies to differentiate their competing agents (i.e., with more classes on the market, companies need to run more head-to-head trials). Concomitantly, the growing number of treatment options means companies also need to pursue more indications for each agents (i.e., approval as a monotherapy, add-on to one other drug, add-on to two or more drugs, etc.). Additionally, Dr. Woerle noted that companies need to conduct larger development programs to investigate candidates in special populations (e.g., people with renal failure), meet different regulatory systems’ clinical development requirements, and answer questions payers have about an agent’s value.

Year of regulatory decision

Candidate

Number of patients enrolled for NDA

1994

metformin

~1,500

1999

rosiglitazone

~7,000

2006

Januvia (sitagliptin)

~3,000

2009

Onglyza (saxagliptin)

~3,500

2011

Tradjenta (linagliptin)

~6,000

2013

Nesina (alogliptin)

~10,500

2013

Invokana (canagliflozin)

~10,000

2013

Farxiga (dapagliflozin)

~10,000

2014

Jardiance (empagliflozin)

~13,000

 

4. During her morning presentation, Dr. Denise Faustman (Harvard Medical School, Boston, MA) did not detail her research on the clinical development of the bacillus Calmette-Guérin (BCG) vaccine’s ability to reverse type 1 diabetes; ClinicalTrials.gov indicates that a phase 2 trial of the agent is to begin this May. In the upcoming five-year study, 120 people ages 18-80 years with type 1 diabetes will be randomized to either BCG or placebo. Those on BCG will receive two vaccinations space four weeks apart in the first year, and an additional vaccination each year for the subsequent four years. The co-primary outcome measures are improvement in A1c from baseline each year and the stabilization or improvement of the BCG arm’s stimulated C-peptide as measured by a mixed meal tolerance test when compared to baseline or the placebo group. The estimated primary completion date is May 2019.  According to Dr. Faustman in a correspondence we had with her, global clinical trials are underway of BCG multi-dosing in several other areas: phase 1 though phase 3 trials are underway using BCG in type 1 diabetes prevention, and phase 3 trials of the agent are being conducted in multiple sclerosis. In her presentation, Dr. Faustman focused her presentation on how she believes the late Dr. George Eisenbarth’s model for the natural history of type 1 diabetes needs revision to account for C-peptide levels being detected in people with long standing type 2 diabetes (as opposed to prior thinking that peoples’ pancreases do not produce insulin more than one-to-two years post-diagnosis).  Dr. Faustman thinks this residual C-peptide should allow people with all stages of diabetes to be included in immune intervention clinical trials, not just people with new onset diabetes. Recent data from her lab is starting to show that these low levels of C-peptide have important clinical significance in protecting from complications.

  • As background, BCG induces the release of cytokine tumor necrosis factor (TNF), which has been shown to selectively destroy insulin-autoreactive T cells. Its use in people with type 1 diabetes rests on the hypothesis that reducing the insulin-autoreactive attack by T cells, induction of beneficial T-regulatory cells and would allow for beta cell regeneration and restoration of insulin secretion. Dr. Faustman published a proof-of-concept study of BCG in September 2012 (n=6 people with type 1 diabetes on placebo or BCG, and 73 reference subjects – 57 of whom had type 1 diabetes), showing a small and transient increase in C-peptide was seen in two-of-the three people who received BCG and a third person who was on placebo but had an acute Epstein-Barr Virus (EBV) infection (causing a spike in TNF similar to that induced by BCG).

5. Dr. Miriam Kidron (Oramed, Jerusalem, Israel) shared expanded results from a small phase 2a in-clinic safety study (n=30) on the company’s oral insulin ORMD-0801. Topline study results were announced in January (read our report). The study (ORA-D-009) was requested by the FDA to prove the safety of Oramed’s candidate (especially with regards to hypoglycemia) before moving into a larger phase 2 study. Dr. Kidron emphasized that the study was not powered to evaluate efficacy. Adding to the difficulty in assessing the efficacy data in this study was the fact that the higher of the two doses tested (24 mg) had a manufacturing malfunction that reduced the efficacy of the dose. On the bright side, we were glad to see that all 30 patients were studied with CGM for the duration of the trial (a paradigm we hope to see applied in more diabetes drug trials). The 16 mg daily dose of ORMD-0801 led to mean glucose reductions (night time, daytime, and fasting) in the range of 20-30 mg/dl. There were no cases of hypoglycemia, no serious adverse events, and non-serious adverse events were relatively balanced between groups. Oramed plans to move on to conduct a phase 2b trial (ORA-D-007), which will be conducted in 200+ patients for 28 days. As opposed to ORA-D-009, this phase 2b trial will be conducted in-home, more closely replicating real-world conditions. Dr. Kidron stated during Q&A that the company hopes ORMD-0801 could be used very early in the treatment cascade for type 2 diabetes, perhaps even before metformin. Oramed also recently issued a press release on the GTC data.

6. NeoStem CMO Dr. Douglas Losordo highlighted that the company is beginning phase 2 testing of its T regulatory cell (Treg) “boost” for people with type 1 diabetes. The therapy is comprised of a patient’s own Tregs which are derived from a sample of the patient’s blood and cultured such that the cell population grows 1,000 fold before being administered to the patient. The rationale behind the therapy is that Tregs help regulate T effector cells (which drive autoimmune attacks) thereby helping to induce self-tolerance. NeoStem’s lead academic collaborator on the therapy is Dr. Jeffrey Bluestone (UC San Francisco, CA), and its phase 1 program (n=14 patients) also involved Dr. Steven Gitelman (UC San Francisco, CA) and Dr. Kevan Herold (Yale University, New Haven, CT) – an extremely well respected group of investigators. Dr. Losordo did not detail the phase 1 results, which are to be presented at ADA by Dr. Gitelman. However, he noted that the therapy had an “acceptable” safety profile and that there was “perhaps a signal of bioactivity.” NeoStem seems to have been pleased with the results, since it is planning to initiate a multicenter TrialNet study of the therapy in 3Q14 (n=40-60 patients). NeoStem is also collaborating with Becton-Dickinson on the program. BD has 11.5% program ownership.

7. Dr. Corinth Auld (Medical Science Liaison, Mercodia, Winston Salem, NC) presented on the significant clinical and investigative advantages of the company’s new C-peptide ELISA assay. Dr. Auld emphasized that the ultrasensitive assay can measure C-peptide levels as low as 1.25 pmol/L, dramatically lower than the classic lower limit of detection of 30 pmol/L used by the DCCT study. The Mercodia assay also boasts precision data of ± 0.11 ng/ml and high specificity to C-peptide (only 1.2% cross reactivity with proinsulin which is the most commonly cross reactive with C-peptide). This precision and specificity data is significant for clinical investigators, who must be confident that any change or increase in C-peptide levels results from interventional therapy rather than an assay’s poor precision or inadvertently measurments of proinsulin levels. This impressive data, in conjunction with past ADA and FDA guidance for C-peptide measurement, poise the Mercodia’s ultrasensitive ELISA assay to see an expanded role in future clinical trials and studies in type 1 diabetes, which will hopefully contribute to improved, more focused treatment therapies.

8. Dr. Richard Oram (University of Exeter, Exeter, UK) discussed his research group’s finding that some patients with long-term type 1 diabetes have low but measurable amounts of C-peptide, as assessed by a unique urine assay. Specifically, his team found that after mixed meal tolerance tests in a cohort of long duration type 1 diabetes patients (n=74), 73% (n=54) of the cohort had detectable 90 minute serum C-peptide levels (>3 pmol/L) using a sensitive assay developed by Roche. Measurments of post-meal urine C-peptide/creatinine ratios (UCPCR) from the UNITED study (n=924) demonstrated that 80% of patients had detectable endogenous insulin. Dr. Oram’s team concluded from these studies that many people with type 1 diabetes still have a small number of functional beta cells. Dr. Oram’s team also found that the median age of diabetes onset was significantly later for those patients with detectable C-peptide levels. These results raise a number of interesting research questions, including: 1) What factors affect the progression of beta cell loss in type 1 diabetes? 2) Is it immune regulation, genetic, early glycemic control, or beta cell regeneration? 3) What is the trajectory of beta cell decline in those patients with retained C-peptide? 4) Could residual beta cells be a target for future therapies? 5) Could knowing which patients have retained insulin should affect how clinicians manage type 1 diabetes. It is notable that both Dr. Oram and Dr. Denise Faustman (see above) found residual insulin secretion in type 1 diabetes patients in separate studies using different ultra-sensitive assays. 

9. Intarcia CEO Mr. Kurt Graves gave an abbreviated 10-minute presentation on the company’s potentially disruptive implantable once or twice-yearly exenatide mini-pump ITCA-650. Intarcia presented at last year’s GTC Bio as well – since then, thanks to a new round of private financing (read our report), the company has become the highest valued private biotech company in history (!). Mr. Graves confirmed previous guidance that the first pivotal phase 3 trial for ITCA-650 will report in September of this year, and that the company is aiming for an NDA-enabling interim analysis of phase 3 data to occur towards the very end of 2015. The company plans to conduct a series of non-pivotal reimbursement-focused real-world head-to-head studies against Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), an SGLT-2 inhibitor plus metformin, and Merck’s DPP-4 inhibitor Januvia (sitagliptin). Mr. Graves walked the audience through the striking interim results of the open-label FREEDOM HBL trial, which were first presented at this year’s JP Morgan Healthcare Conference. For background, the data demonstrated an impressive mean A1c reduction of 3.2%, albeit from a high baseline of 10.9%. During this portion of the presentation, we noticed a great deal of impressed looks in the audience. In a later Q&A session, an audience member expressed disbelief that a single therapy could achieve such marked A1c reductions. We imagine that interest in ITCA-650 will continue to grow when open-label phase 3 results are presented at this year’s ADA.

10. Dr. Sethu Reddy (Cleveland Clinic, OH) moderated a panel on “Partnering with Academia,” which fostered frank discussion on the challenges of industry-academia collaborations. Ms. Lita Nelsen (Director, Technology Licensing Office, MIT, Cambridge, MA) explained that since the recession, venture capital financing of biotech companies has dwindled, forcing large pharmaceutical companies to look towards academia in order to keep their pipelines full. Ms. Nelsen emphasized that academic institutions like MIT want to work with industry, but they have several non-negotiables. For example, academic groups cannot agree to keep data secret for long periods of time, as their focus is on the publication and dissemination of knowledge. Additionally, academic institutions face legal limitations: Ms. Nelsen noted that IRS rules preclude academic groups from pre-negotiating royalties with industry. Academic institutions must balance working with and supporting industry, while not damaging their reputation as unbiased research institutions. One academic center that appears to be walking this tight rope well is the Joslin Diabetes Center. Mr. John Brooks (President and CEO, Joslin Diabetes Center, Boston, MA) described how Joslin is working to be involved throughout the process of drug development and delivery. For example, two months ago, Joslin launched a branch that is focused on working on industrial clinical trials. The group helps with protocol development (including the integration of economic measures into safety/efficacy studies), in addition to study execution. Mr. Brooks indicated that Joslin already has eight customers for this service. Additionally, Mr. Brooks acknowledged the potential posed by co-location programs, where small biotechs can work in proximity to industry groups and the two sides can frequently interact.

 

Honorable Mention

Earlier in the day Dr. Reddy gave an (appropriately) engaging talk on “engaging the customer” (defining the term “customer” broadly) in drug development. Emphasizing the changing landscape of diabetes, Dr. Reddy suggested that the “FDA approval is no longer the touchdown, but rather only the first down.” He noted that diabetes drugs (in many ways) face a higher bar than drugs for orphan diseases. Successful diabetes drugs must be differentiated, innovative, disease altering, valuable to both payers and patients, and easily assimilated into the current healthcare system. To expand on this assimilation, Dr. Reddy brought his own clinical experience to the table, explaining, “It is phenomenally energizing to see the creative juices flowing in this room around new innovations, but when I’m sitting in front of my patient and I have eight different therapies and no clear algorithm on which one, when, and how to combine these therapies, it becomes very difficult… especially when new therapies are only incrementally beneficial from the last.” Those words, we imagine, apply to the vast majority of providers who treat diabetes patients, many of whom are in primary care. Dr. Reddy challenged the audience to broaden the term “customer” beyond just patients but to also include physicians, insurers, government, hospitals, integrated delivery systems (IDS), pharmacies, and distributors, each of which have different perspectives, interests, limitations, and needs. An increased need to appeal to payers is certainly a major trend we are seeing in the diabetes drug development and commercialization process, and we agree with Dr. Reddy that securing reimbursement is becoming almost like a second required approval for a drug. This trend increases the need for more overlap in trials that support registration and those that support reimbursement.

--by Hannah Deming, Jenny Tan, Manu Venkat, and Kelly Close