Brainstorm Cell Therapeutics (OTCQB:BCLI) is an Israeli biotech company developing a stem cell-based treatment for amyotrophic lateral sclerosis (ALS), a progressive chronic neurological disease that attacks nerve cells responsible for controlling skeletal muscles. With only one FDA-approved drug [Sanofi Aventis' (NYSE:SNY) Rilutek], which offers few benefits for patients, ALS patients are in dire need for new therapies.
Brainstorm's treatment is based on autologous (patient's own cells) transplantation of adult bone marrow-derived mesanchimal stem cells that are differentiated using the company's proprietary technology, NurOwn™, into cells that secrete neurotrophic factors.
BCLI recently reported final results from the first stage of its Phase I/IIa clinical study that evaluated the company's ALS treatment in 12 patients. The study demonstrated that the stem cells transplantation resulted in "a significantly slower decline in overall clinical and respiratory function, as measured by the ALS Functional Rating Score (ALSFRS-R) and Forced Vital Capacity (FVC) score respectively, in the six patients that received an intrathecal injection of the cells in the six months following treatment, as compared to the three months preceding treatment". The study also tested, and initially confirmed, the safety of the treatment protocol.
BCLI's stock, which has dropped about 4% from the beginning of the year, responded to the good clinical news with a 6% increase, with trading volumes up 5 fold compared to the 3 months average. The modest stock movement following the company's announcement could be explained by the shortage of cash at hand - around $4m, which might mean that a financing round is right around the corner.
The results presented by Brainstorm are very encouraging, both for the company and the patients, but are preliminary, and require further validation. In the second stage of the ALS study, which began in February this year, 12 additional ALS patients will be administered with Brainstorm's stem cells in increasing doses. The first cohort of four patients is expected to complete treatment by the end of April. BCLI is currently awaiting FDA approval to expand its ALS clinical development to the U.S., which is planned to commence during 2013. The NurOwn technology for treatment of ALS has been granted orphan-drug designation by the FDA.
Brainstorm's major competitor in the ALS cell therapy field is Neuralstem (NYSEMKT:CUR), whose treatment is based on human spinal cord-derived neural stem cells (NSI-566). Neuralstem completed a Phase I/IIa study in ALS patients in February 2013 and also reported of promising results in several patients, in which the disease was stabilized for nearly one year. Neuralstem is expected to commence an ALS Phase II trial during 2013.
BCLI is one of several Israeli companies that are advancing R&D programs with stem cell-based therapeutics (table 1). Interestingly, Israeli companies take up a surprising share among companies that develop stem cell-based therapies, especially when considering the small size of this country. This could be attributed to the strong presence of stem cells research in Israeli academic institutes, support from the government for stem cell research and lack of ethical barriers for the use of embryonic stem cells, as experienced by U.S. researchers during the Bush Administration. In the second part of this article we will briefly review several Israeli stem cell companies.
Table 1: summary of leading Israeli companies developing stem cell therapies:
BrainStorm Cell Therapeutics
Cell Cure Neurosciences*
Tel-Aviv Stock Exchange
Tel-Aviv Stock Exchange
* Private company. Major holdings by public companies is parentheses.
Pluristem is the most covered Israeli stem cell company and a leading developer of placenta-derived stem cell therapies. The company's PLX cells are grown using a proprietary 3D micro-environmental technology and are a unique off-the-shelf product that requires no tissue matching prior to administration.
Pluristem's comprehensive clinical plan focuses primarily on peripheral artery disease (PAD), and includes a Phase II/III multinational pivotal study with 450 critical limb ischemia patients set to begin this year, as well as a US Phase II study with intermittent claudication (a less severe form of PAD) patients in progress. In addition, in late 2012 PSTI has initiated a Phase I/II clinical trial in patients recovering from to hip replacement surgery. This study will evaluate the PLX cells in improvement of gluteal buttock muscle injury rehabilitation. Patient enrollment for this study, and potentially top-line results, are expected until the end of 2013. Finally, Pluristem announced it intends to enter the hematology field. The FDA Orphan drug designation for treatment of aplastic anemia which was granted for the company this February may imply on the specific hematological indication the company plans to target.
In addition to its in-house clinical programs, in mid-2011 Pluristem has signed a $62 million license agreement with United Therapeutics Corporation (NASDAQ:UTHR) for the use of the PLX cells to develop and commercialize a cell-based product for the treatment of Pulmonary Hypertension. Apart from the upfront and milestone payments, UHTR will reimburse PSTI for development costs, purchase commercial supplies from Pluristem upon commercialization of the product and will pay Pluristem royalties from its gross profits.
2012 has been a good year for PSTI's stock, with a 25% increase. Since the beginning of 2013 the stock has been fluctuating in the $3-3.4 range, while analysts' price targets for PSTI range between $5 and $10. Following a secondary offering in mid-September 2012, in which the company raised $32 million, Pluristem has approximately $66 million in the bank, plus an ATM agreement with MLV & Co of up to $95 million. This means the Pluristem is not expected to dilute its investors in the near future.
Cell Cure Neurosciences
Cell Cure is a private company with significant holdings by BioTime Inc. (NYSEMKT:BTX) and Hadasit Bio Holdings, with 62.6% and 21% respectively. Cell Cure develops therapies for retinal and neural degenerative diseases, based on human embryonic stem cells (hESCs).
The company's lead product is OpRegen® for age-related macular degeneration (dry-AMD), an incurable eye disease that is the leading cause of blindness in the aging population, affecting around 10 million Americans. OpRegen® is comprised of hESCs that are differentiated into retinal pigmented epithelial cells and are transplanted under the retina as a suspension or supported on a membrane (OpRegen®-Plus). Cell cure recently announced that IND filing and initiation of clinical trials are expected during 2013.
Initiation of clinical trials will place Cell Cure in direct competition with StemCells Inc. (NASDAQ:STEM) and Advanced Cell Technology Inc. (ACTC.OB), both are developing similar hESC-based dry-AMD therapies. Cell Cure's edge in this competition might come from an agreement the company holds with Teva Pharmaceutical Industries (NYSE:TEVA), which provides the latter the option to develop and commercialize this product, as well as form the backing of BioTime, which has accumulating experience and know how in the regenerative medicine field through its subsidiaries.
Another biotech focused on hESCs that targets two major medical applications: regenerative medicine and drug-screening. Kadimastem's chief scientist is Prof. Michel Revel, who have led the biotechnological development of Interferon-beta therapy for the treatment of multiple sclerosis (MS) and is the original developer of the blockbuster MS drug, Rebif.
On the regenerative medicine front, Kadimastem's lead product is based on hESCs differentiated into pancreatic beta- and alpha-cells that form islets of Langerhans-like clusters. These cell clusters are developed as a treatment for type 1 and late-type 2 diabetes as a replacement for the damaged insulin producing cells.
Kadimastem also utilizes its unique hESC-derived oligodendrocytes and neurons co-cultures as a drug-screening platform. This system is used as a functional assay for human oligodendrocytes, enabling the screening of potential drugs that promote the repair of damaged myelin - a key pathological process in MS. Kadimastem has signed a five year, 5 million Euro agreement with Merck Serono, a division of Merck KGaA (OTCPK:MKGAY), for the use of its drug-screening platform to discover new oral drugs for the treatment of MS.
As far as the biotech dream goes, stem cell companies represent one of the biggest dreams, that may change the face of medicine and provide therapies to currently incurable diseases. However, as all dream companies, the stem cell dream comes with great risks and challenges.