My mother was diagnosed with Multiple Sclerosis (MS) when I was five-years-old. At the time, there were no effective treatments for the disease. My mother tried every medication doctors prescribed, an experimental surgery, and even non-conventional therapies. Everything failed. I tried to help her too, using the tools I had as a child – hope, prayers, and my imagination. I imagined ways to make her better. And I hoped and prayed with all of my might that she would stop seeing two of everything, that she would stop shaking, and that she would be able to walk and talk again. MS is an autoimmune disease, and the concept of autoimmunity was incomprehensible to me. Why would a body do that to itself? Why can’t we make it stop?My mother’s case, unlike a lot of cases of MS, had almost no remissions. Her condition worsened until her death in 1989. Less than two years after she died, I met Mike, the man who would become my husband. With Mike I began to build a new life, a good life. My obsessive thinking about autoimmunity moved to the background of my mind until Mike started to lose weight and was always thirsty.
Six months later, twenty pounds lighter, with blurred vision and numb feet, Mike was diagnosed with type 1 diabetes, an autoimmune disease which destroys the body’s insulin producing beta cells. We hardly knew what that meant, but we did know a diabetes cure was nowhere in sight. Thankfully, unlike my mother’s MS, diabetes was treatable. In fact, Mike’s doctor told him that there was a drug in clinical trials that might be able to stop the progression of diabetes. Stop the progression. Though not in the same context, I’d been waiting to hear those words for most of my life. They sounded too good to be true and they filled me with hope. We asked no questions. Mike underwent a number of tests after which he was accepted into the clinical trial for a drug known as Diapep277.
Diapep277 was discovered in 1990 by Professor Irun Cohen and his team at the Weizmann Institute’s Department of Immunology. They were studying the mechanism by which the immune system attacks and destroys the insulin producing beta cells in the pancreas. In mouse studies they discovered that heat shock protein 60 (HSP60) was involved in the attack. HSP60 is a ubiquitous protein, part of a highly conserved family of intracellular chaperones, but with a special location in insulin-secretory granules of beta cells. HSP60, Cohen found, works like an antigen, that is, it triggers the T-cells in the immune system to attack. Cohen’s team also found that a small peptide fragment of HSP60, p277, works as a signal to the immune system to stop the immune attack on the beta cells, thereby preventing the progression of diabetes. Cohen and his team were led to p277, he told me, by studying the responses of T-cells and antibodies to HSP60 in mice that spontaneously develop a form of type 1 diabetes.
When Mike enrolled in the Phase II trail of Diapep277, he was told it was a potential diabetes vaccine. This notion of vaccine was somewhat confusing. Mike, after all, had type 1 diabetes. Diapep277 wasn’t going to prevent it like the chicken pox vaccine prevents chicken pox. But the notion of a vaccine is more complex than that. “The immune system, like the brain, learns from experience,” said Cohen. “A vaccine is a signal or set of signals that teaches the immune system how to respond to a particular situation. We could call Diapep a ‘therapeutic vaccine’ – probably it would be clearer to call it a specific modulator of the immune system – a signal that helps the immune system to make desirable decisions in how it should relate to the body.”
Mike’s Diapep277 trial took place in 2002-2003. The study coordinator told him the participants were divided into three groups – high dose recipients, low dose recipients, and a placebo group. Then, Mike did not know which group he was in. He now knows he did receive Diapep277. Throughout the study, doctors monitored Mike closely. They were checking for residual beta cell function by a measurement of C-peptide (C-peptide is a protein produced along with insulin, and its presence in the body is a sign of insulin secretion, or beta cell function.) In order to measure beta cell function, Mike was given glucagon injections and then blood was drawn to learn his body’s response to the glucagon. The study also measured his HbA1c. “What was most surprising was the lack of side effects,” says Dr. Mariela Glandt who led a follow-up trial to Mike’s under Prof. Itamar Raz at Hadassah Hosptial in Jerusalem. “Patients had no complaints.”
Phase II results were promising and a combined analysis of all the adult phase II studies revealed that DiaPep277 significantly inhibits the decline in stimulated C-peptide secretion, thus preserving endogenous insulin secretion, or in simple terms, it slows the progression of type 1 diabetes.
In 2007, Andromeda Biotech Ltd., a then newly formed wholly owned subsidiary of Clal Biotechnology Industries, purchased the Diapep277 program. Two years later, Teva Pharmaceutical took an equity position in Andromeda. Teva licensed worldwide rights to DiaPep277 from Andromeda Biotech and invested $170 million in the company last year to fund a clinical trial to confirm earlier results for DiaPep277. (Coincidentally, for me, Teva’s longtime blockbuster drug has been Copaxone, for the treamtment of MS.)
In November 2011, Andromeda Biotech announced Phase III study results equally, if not more promising, than the Phase II results. The new results from patients who were treated with DiaPep277 showed that the study has met its primary endpoint- significant preservation of C-peptide levels demonstrated in patients treated with DiaPep277 compared to the placebo arm.
The study also achieved a key secondary endpoint, showing that a greater proportion of DiaPep277 treated patients maintained good metabolic control compared to the placebo, measured by HbA1c levels equal or less than 7% at the end of the study. “The results I have seen thus far are better than I expected,” said Cohen. “Large clinical trials have so many confounding variables that even treatments that are effective can fail to reach statistical significance. In this case, all the declared endpoints seem to have been achieved.”
For scientists and researchers involved in a clinical trial, achieving declared endpoints is indeed a success. The patient, however, doesn’t necessarily measure success in the same way. Mike wears an insulin pump, checks his blood sugar ten times a day, and battles both episodes of hyper and hypoglycemia. “I ate rice last night and woke up with a blood sugar of 200, despite taking insulin,” Mike said. “This morning I went out for a one-hour run and my blood sugar stayed at 190 the entire time.”
If Diapep277 did anything to slow down the progression of Mike’s diabetes, it was never noticeable. If it will help in the long-term, we don’t know. Over the years, Mike’s study hasn’t followed him. And we wonder how long the effects of the Diapep277 injections lasted. I asked Cohen about this. “The effect seems to need boosting every three months or so,” he said.
Also interesting to note is that a 2007 study showed that in children, treatment with Diapep277 “appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.” Cohen said a more thorough analysis of the data indicates that there is a positive response in the children who do not carry the most decisive susceptibility genes. “Apparently, the disease progresses too quickly for Diapep to help in the children who have a more intense, accelerated course of beta cell destruction. I would like to believe that the solution will be to detect and treat persons early in the course of the autoimmune reaction, before the loss of beta cells become irreversible.”
The key, then, if Diapep277’s continuing trials prove successful, will be to identify the right people and treat them at the right time- as early in the disease process as possible. But the development of screening tests is a complicated and expensive process. “I’d been sick for more than six months when I was diagnosed with diabetes,” Mike says. My fasting blood sugar was over 400. My HbA1c was 15.7%. Maybe I was too far gone to be helped by Diapep. Maybe if I’d received the injections as soon as I started to feel thirsty, there would have been a noticeable difference.”